WO2023067322A1 - Modulateurs tricycliques de la gpr65 - Google Patents

Modulateurs tricycliques de la gpr65 Download PDF

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Publication number
WO2023067322A1
WO2023067322A1 PCT/GB2022/052644 GB2022052644W WO2023067322A1 WO 2023067322 A1 WO2023067322 A1 WO 2023067322A1 GB 2022052644 W GB2022052644 W GB 2022052644W WO 2023067322 A1 WO2023067322 A1 WO 2023067322A1
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Prior art keywords
alkyl
alkoxy
aryl
cycloalkyl
heterocycloalkyl
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PCT/GB2022/052644
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English (en)
Inventor
Tom Mccarthy
Alan Naylor
David Miller
Gavin MILNE
Maria IEVA
Tobias Mochel
Yannick ESVAN
John Feutrill
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Pathios Therapeutics Limited
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Priority claimed from GBGB2114866.3A external-priority patent/GB202114866D0/en
Priority claimed from GBGB2117501.3A external-priority patent/GB202117501D0/en
Priority claimed from GBGB2208626.8A external-priority patent/GB202208626D0/en
Priority claimed from GBGB2211546.3A external-priority patent/GB202211546D0/en
Priority claimed from GBGB2213798.8A external-priority patent/GB202213798D0/en
Application filed by Pathios Therapeutics Limited filed Critical Pathios Therapeutics Limited
Priority to CA3233474A priority Critical patent/CA3233474A1/fr
Priority to AU2022369094A priority patent/AU2022369094A1/en
Publication of WO2023067322A1 publication Critical patent/WO2023067322A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems

Definitions

  • the present invention relates to compounds that are capable of modulating GPR65.
  • the compounds have potential therapeutic applications in the treatment of a variety of disorders, including proliferative and immune disorders.
  • GPR65 is a Gs-coupled G protein-coupled receptor (GPCR) that is primarily expressed in immune cells and is activated by acidic extracellular pH to cause increases in cytoplasmic cyclic adenosine monophosphate (cAMP) (Wang, 2004). It has long been known that tumours typically undergo a switch in cellular metabolism from oxidative phosphorylation to aerobic glycolysis, which in turn results in an acidic extracellular microenvironment (Damaghi, 2013). Recently, it has been shown that this acidic microenvironment causes GPR65 activation in tumour-associated macrophages, resulting in an increase in cytoplasmic cAMP leading to transcription of the inducible cAMP early repressor (ICER).
  • GPCR Gs-coupled G protein-coupled receptor
  • tumour necrosis factor alpha TNFa
  • GPR65 locus mutations in the GPR65 locus are associated with several autoimmune diseases, such as multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, and Crohn's disease (Gaublomme, 2015).
  • autoimmune diseases such as multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, and Crohn's disease (Gaublomme, 2015).
  • EAE disease autoimmune encephalomyelitis
  • GPR65 appears to act through ICER to promote an anti-inflammatory and tumour- permissive phenotype in tumour associated macrophages and an inflammatory Th17 phenotype in CD4+ T cells that is associated with autoimmune disease.
  • GPR65 signalling therefore, represents an attractive pathway for therapeutic intervention for the treatment of both cancer and autoimmune diseases. There is therefore an ongoing need to develop new small molecule GPR65 modulators.
  • WO 2021/245427 discloses a series of small molecule GPR65 modulators.
  • the present invention seeks to provide further compounds that are capable of modulating GPR65.
  • such compounds have potential therapeutic applications in the treatment of a variety of disorders, including proliferative disorders and immune disorders, as well as asthma and chronic obstructive pulmonary disease.
  • the presently claimed compounds may also exhibit one or more of the following properties: enhanced activity against GPR65 (also in native cells), better in vitro selectivity and toxicity profiles and/or enhanced oral pharmacokinetic profiles relevant to chronic once daily oral administration.
  • a first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: ring B is: a monocyclic aromatic group; or a monocyclic or bicyclic heteroaromatic group, each of which is optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, NHCO-aryl, -(CH 2 )q-O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and CO 2 -alkyl, wherein said aryl, heteroaryl, heterocycloalky
  • Z is CR 12 ;
  • Y is CR 10 R 10 ', wherein R 10 and R 10 ' are each independently selected from H, F, alkyl, and haloalkyl; R a and R b are each independently selected from H and alkyl;
  • Re is selected from H, alkyl, cycloalkyl and hydroxyalkyl
  • R 12 is selected from H, alkyl, haloalkyl, halo, OH and O-alkyl; and R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 ', and R 16 are each independently selected from H, alkyl, and alkoxyalkyl.
  • Another aspect of the invention relates to a compound of formula (If), or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • R 11 is selected from H, alkyl, haloalkyl, halo, OH and O-alkyl; and B, Y, Z, R a and R b are as defined hereinabove.
  • Another aspect of the invention relates to a compound of formula (Ij) or a pharmaceutically acceptable salt or solvate thereof,
  • Y is CR 10 R 10 ', wherein R 10 and R 10 ' are each independently selected from H, F, alkyl, and haloalkyl; R a and R b are each independently selected from H and alkyl; R 1 ', R 2 ', R 4 ' and R 5 ' are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH and halo;
  • R 3 ' is a pyridinyl group substituted by one or more substituents selected from CN, haloalkyl, haloalkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, O-(CH 2 )q-heterocycloalkyl, alkoxy-alkoxy, alkylamino-alkoxy, dialkylamino-alkoxy, alkoxy-alkyl and O-(CH 2 ) P -cycloalkyl, wherein said cycloalkyl group is optionally substituted by one or more halo, alkyl or alkoxy groups, and wherein said pyridinyl is optionally further substituted by one or more substituents selected from halo, alkyl and alkoxy;
  • R 6 ' is H or alkyl, more preferably H;
  • R 7 , R 8 and R 9 are each independently selected from H, halo and alkyl;
  • R 13 and R 13 ' are each independently selected from H, alkyl, and alkoxy-alkyl; and
  • p and q are each independently 0 to 3.
  • the presently claimed compounds are capable of modulating GPR65, thereby rendering the compounds of therapeutic interest in the treatment of various disorders, for example, in the field of oncology, immuno-oncology, and immunology.
  • Another aspect of the invention relates to a compound or pharmaceutically acceptable salt or solvate thereof, as described herein for use as a medicament.
  • Another aspect of the invention relates to a compound or pharmaceutically acceptable salt or solvate thereof, as described herein for use in treating or preventing a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).
  • a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory distress syndrome
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described herein and a pharmaceutically acceptable diluent, excipient, or carrier.
  • Another aspect of the invention relates to a pharmaceutical composition as described herein for use as a medicament.
  • Another aspect of the invention relates to a pharmaceutical composition as described herein for use in treating or preventing a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).
  • a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory distress syndrome
  • Another aspect of the invention relates to a method of treating a disorder, comprising administering to a subject a compound or a pharmaceutical composition as described herein.
  • the present invention relates to compounds that are capable of modulating GPR65.
  • Alkyl is defined herein as a straight-chain or branched alkyl radical, preferably C 1-20 alkyl, more preferably C 1-12 alkyl, even more preferably C 1-10 alkyl or C 1-6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. More preferably, the alkyl is a C 1-3 alkyl.
  • Cycloalkyl is defined herein as a monocyclic alkyl ring, preferably, C 3-7 -cycloalkyl, more preferably C 3-6 -cycloalkyl. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or a fused bicyclic ring system such as norbornane.
  • aryl refers to a C 6-12 aromatic group, which may be a monocyclic or fused bicyclic group, including benzocondensed groups. Examples include phenyl and naphthyl.
  • Haloalkyl is defined herein as a straight-chain or branched alkyl radical as defined above, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, that is substituted with one or more halogen atoms (that may be the same or different), such as fluorine, chlorine, bromine, and iodine.
  • halogen atoms that may be the same or different
  • the haloalkyl is a C 1-20 haloalkyl, more preferably a C 1-12 haloalkyl, even more preferably a C 1-10 haloalkyl or a C 1-6 haloalkyl, or a C 1-3 haloalkyl.
  • Preferred examples are CF 3 and CHF 2 , with CF 3 being particularly preferred.
  • Alkoxy is defined herein as an oxygen atom bonded to an alkyl group as defined above, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy and hexoxy.
  • the alkoxy is a C 1-20 alkoxy , more preferably a C 1- 12 alkoxy, even more preferably C 1-10 alkoxy or a C 1-6 alkoxy, or a C 1-3 alkoxy.
  • a particularly preferred example is methoxy (-OCH 3 ).
  • Alkoxy-alkyl is defined as an alkyl group as that is substituted by one or more alkoxy groups, e.g. MeOCH 2 CH 2 -.
  • Alkoxy-alkoxy is defined as an alkoxy group that is substituted by one or more further alkoxy groups, e.g.
  • MeOCH 2 CH 2 O- also referred to as an ether group.
  • Haloalkoxy is defined herein as an alkoxy group as described above that is substituted with one or more halogen atoms (that may be the same or different), such as fluorine, chlorine, bromine, and iodine.
  • Heteroaryl or “heteroaromatic” is defined herein as a monocyclic or bicyclic C2-12 aromatic ring comprising one or more heteroatoms (that may be the same or different), such as oxygen, nitrogen or sulphur.
  • suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyridinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl etc.
  • Heterocycloalkyl refers to a cyclic aliphatic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur, which is optionally interrupted by one or more - (CO)- groups in the ring and/or which optionally contains one or more double bonds in the ring.
  • the heterocycloalkyl group is monocyclic or bicyclic.
  • the heterocycloalkyl group is a C 3-7 -heterocycloalkyl, more preferably a C 3-6 -heterocycloalkyl.
  • the heterocycloalkyl group is a C 4-7 -heterocycloalkyl, more preferably a C 4-6 -heterocycloalkyl.
  • Preferred heterocycloalkyl groups include, but are not limited to, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl and tetrahydropyranyl.
  • heterocycloalkyl groups containing a CO group and one or more double bonds include 3-oxo-3,4-dihydro-2H-benzo[b][1 ,4]oxazin-6-yl, oxoisoindolinyl, oxoindolinyl, 1-oxo-1 ,2,3,4-tetrahydroiso-quinolin-6-yl, 1-oxo-1 ,2,3,4-tetrahydroisoquinolin- 6-yl and the like.
  • Alkyl is defined herein as an alkyl group as defined above substituted by one or more aryl groups as defined above.
  • alkyl is C 1 -C 6 alkyl
  • haloalkyl is C 1 -C 6 haloalkyl
  • alkoxy is C 1 -C 6 alkoxy
  • haloalkoxy is C 1 -C 6 haloalkoxy.
  • the compounds of the invention comprise a structure wherein an optionally substituted 6- membered nitrogen-containing ring is fused to a bicyclic nitrogen-containing moiety to form a tricyclic structure.
  • the resulting tricyclic structure can exist in two different configurations as depicted below:
  • the invention encompasses the compounds in either of the above configurations, as well as mixtures thereof, including racemic mixtures.
  • the structure can, for example, be represented, as follows (where R a and R b groups are omitted for clarity):
  • the invention encompasses the compounds in the above configuration, as well the corresponding enantiomers thereof, and mixtures thereof, including racemic mixtures.
  • specific examples of compounds according to the invention depicted in the above configuration (1.3) refer to mixtures of both enantiomers (in particular, the racemate), whereas the respective enantiomers - where these have been synthesised or separated - are depicted as either configuration (1.1) or configuration (1.2) with wedged bonds or dashed bonds respectively.
  • the compounds described herein contain an optionally substituted 6-membered ring, which is fused to the bicyclic nitrogen-containing moiety to form a tricyclic structure.
  • compounds of formula (I) where R 6 is H can exist in the following tautomeric forms:
  • the present invention relates to compounds of formula (I) as defined above.
  • p and q are each independently 0 or 1 . In one preferred embodiment, p and q are both 0.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: ring B is: a monocyclic aromatic group; or a monocyclic or bicyclic heteroaromatic group, each of which is optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl, NHCO-aryl, O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and CO 2 -alkyl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, O-cycl
  • Z is CR 12 ;
  • Y is CR 10 R 10 ', wherein R 10 and R 10' are each independently selected from H, F, alkyl, and haloalkyl; R a and R b are each independently selected from H and alkyl;
  • Re is selected from H, alkyl, cycloalkyl and hydroxyalkyl
  • R 12 is selected from H, alkyl, haloalkyl, halo, OH and O-alkyl
  • R 13 , R 13 ' , R 14 , R 14 ' , R 15 , and R 15 ' and R 1 e are each independently selected from H, alkyl, and alkoxyalkyl.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: ring B is: a monocyclic aromatic group; or a monocyclic or bicyclic heteroaromatic group, each of which is optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO 2 -alkyl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-
  • Z is C R 12 ;
  • Y is CR 10 R 10 ', wherein R 10 and R 10 '' are each independently selected from H, F, alkyl, and haloalkyl; R a and R b are each independently selected from H and alkyl;
  • R 6 is selected from H, alkyl, cycloalkyl and hydroxyalkyl
  • R 1 2 is selected from H, alkyl, haloalkyl, halo, OH and O-alkyl
  • R 13 , R 13 ' , R 14 , R 14 ' , R 15 , and R 15 ' and R 16 are each independently selected from H, alkyl, and alkoxyalkyl.
  • m is an integer from 1 to 3, more preferably 1 or 2, more preferably 1.
  • R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 ' and R 1 e are each independently selected from H and alkyl. More preferably, R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 ' are all H.
  • R 1 e is alkyl, more preferably Me.
  • ring B is: a monocyclic aromatic group; or a monocyclic or bicyclic heteroaromatic group, each of which is optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO 2 -alkyl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CON
  • Z is CR 12 ;
  • Y is C R 10 R 10 ', wherein R 10 and R 10 ' are each independently selected from H, F, alkyl, and haloalkyl; R a and R b are each independently selected from H and alkyl;
  • Re is selected from H, alkyl, cycloalkyl and hydroxyalkyl
  • R 1 2 is selected from H, alkyl, haloalkyl, halo, OH and O-alkyl
  • R 13 , R 13 ', R 14 , R 14 ', R 15 , and R 15 ' are each independently selected from H, alkyl, and alkoxyalkyl.
  • ring B is: a monocyclic aromatic group; or a monocyclic or bicyclic heteroaromatic group, each of which is optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO 2 -alkyl, wherein said aryl, heteroaryl, O-cycloalkyl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl and alkoxy;
  • Z is CR 12 ;
  • Y is CR 10 R 10 ', wherein R 10 and R 10' are each independently selected from H, F, alkyl, and haloalkyl; R a and R b are each independently selected from H and alkyl;
  • Re is selected from H, alkyl, cycloalkyl and hydroxyalkyl; and R 1 2 is selected from H, alkyl, haloalkyl, halo, OH and O-alkyl.
  • R a and R b are each independently selected from H and methyl. In one preferred embodiment, one of R a and R b is alkyl (more preferably methyl) and the other is H. In one particularly preferred embodiment, R a and R b are both H.
  • Y is CR 10 R 10 ', where R 10 and R 10 ' are each independently selected from H, F, Me and CF 3 , and more preferably selected from H, F and Me. In one preferred embodiment, Y is selected from CH 2 , CHF and CHMe. More preferably, Y is CH 2 .
  • Re is selected from H, methyl and hydroxymethyl, and is more preferably H.
  • R 12 is H or alkyl.
  • Z is CH (i.e. R 12 is H), and the compound is of formula (le), or a pharmaceutically acceptable salt or solvate thereof: wherein Re, R a , R b , Y and B are as defined above.
  • ring B is a phenyl group optionally substituted by one or more substituents each independently selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O- heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO 2 -alkyl, wherein said aryl, heteroaryl, O-cycloalkyl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl and alkoxy.
  • the compound is of formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein
  • R1 , R 4 , and R 5 are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, and halo;
  • R 2 and R 3 are each independently selected from H, OH, halo, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl, NHCO-aryl, -(CH 2 )q-O- heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and CO 2 -alkyl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, NHCO-aryl, -(CH 2
  • R 1 , R 4 , and R 5 are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, and halo;
  • R 2 and R 3 are each independently selected from H, halo, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl, NHCO-aryl, O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and CO 2 -alkyl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, NHCO-aryl, O-heteroaryl, CONH-aryl, aryloxy-alkyl, O- aralkyl, and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, alk
  • Z, Y, R a , R b , m and R 6 are as defined above; and R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 ' and R 1 e are each independently selected from H, alkyl, and alkoxyalkyl.
  • R 3 is an aryl or heteroaryl group each of which is optionally further substituted by one or more groups independently selected from halo, haloalkyl, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH 2 )m-NHSO 2 -alkyl, CO 2 R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, O-heterocycloalkyl, heteroaryl, alkoxy-alkoxy, O- (CH 2 ) P -cycloalkyl, where in the latter group, said cycloalkyl group is optionally further substituted by one or more halo, haloalkyl group is
  • R 3 is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrazinyl, [1 ,2,5]thiadiazolo[3,4-b]pyridinyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindolinyl, oxoindolinyl, imidazolyl, benzooxazinyl, pyrrolopyridinyl, oxotetrohydroisoquinolinyl, benzo[c][1 ,2,5]oxadiazolyl, benzo[c][1 ,2, 5]thiadiazolyl , benzo[d]oxazolyl, pyridazinyl, oxazolyl, isothiazolyl, benzo[d]isooxazolyl, benzo[c]isothiazolyl, imidazo[1 ,5-a]pyr
  • R 3 is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindolinyl, oxoindolinyl, imidazolyl, benzooxazinyl, pyrrolopyridinyl, oxotetrohydroisoquinolinyl, benzo[c][1 ,2,5]oxadiazolyl, benzo[c][1 ,2,5]thiadiazolyl, benzo[d]oxazolyl, pyridazinyl, oxazolyl, isothiazolyl, benzo[d]isooxazolyl, imidazo[1 , 5-a]pyridi nyl , [1 ,2,5]oxadiazolo[3,4-b]pyridinyl, benzo[c]isoxazolyl, imidazo
  • R 3 is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindolinyl, oxoindolinyl, imidazolyl, benzooxazinyl, pyrrolopyridinyl, oxotetrohydroisoquinolinyl, benzo[c][1 ,2,5]oxadiazolyl, or 2H- benzo[b][1 ,4]oxazin-3(4H)-onyl; each of which is optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 - alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl
  • R 2 and R 3 are each independently selected from H, halo, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, heterocycloalkyl, O- heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl and CO 2 -alkyl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocyclo
  • said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl and alkoxy.
  • R 1 and R 4 are both H.
  • R 5 is selected from H, F, Me, MeO, Cl, OH and CN, and is preferably H or F, more preferably F.
  • R 2 is selected from Cl, Br, and CF 3 , more preferably Cl.
  • R 1 and R 4 are selected from halo and haloalkyl (more preferably halo) and R 2 and R 5 are both H.
  • R 1 is F
  • R 2 is H
  • R 4 is Cl
  • R 5 is H
  • ring B is:
  • R 3 is defined as set out below. In one preferred embodiment of formula (la), R 3 is selected from:
  • each of which is optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl,
  • R 1 and R 4 are selected from halo and haloalkyl (more preferably halo) and R 2 and R 5 are both H. More preferably, R 1 is F, R 2 is H, R 4 is Cl and R 5 is H.
  • R 3 is selected from the above groups (a-1)-(a-38), each of which is optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl- NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH 2 )m-NHSO 2 -alkyl, CO 2 R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy, heterocycloalkyl, and heteroaryl, wherein R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 ' and R 16 are each independently selected from H, alkyl, and alkoxyalkyl.
  • R 1 and R 4 are selected from halo and haloalkyl (more preferably halo) and R 2 and R 5 are both H. More preferably, R 1 is F, R 2 is H, R 4 is Cl and R 5 is H.
  • R 3 is selected from the above groups (a-1)-(a-28), each of which is optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl- NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH 2 )m-NHSO 2 -alkyl, CO 2 R 16 , alkoxy-alkyl, O-cycloalkyl, haloalkoxy and heteroaryl, wherein R 13 , R 13 ', R 14 , R 14 ', R 15 , R 15 ' and R 16 are each independently selected from H, alkyl, and alkoxyalkyl.
  • R 1 and R 4 are selected from halo and haloalkyl (more preferably halo) and R 2 and R 5 are both H. More preferably, R 1 is F, R 2 is H, R 4 is Cl and R 5 is H.
  • R 3 is selected from the above groups, each of which is optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl and heteroaryl.
  • R 3 is selected from groups (a-1)-(a-16) above, each of which is optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl and heteroaryl.
  • R 3 is a pyridinyl group, optionally substituted as above for definitions (a-1)-(a-39).
  • R 3 is a 3-pyridinyl group, optionally substituted as above for definitions (a-1)-(a-39).
  • R 1 and R 4 are selected from halo and haloalkyl (more preferably halo) and R 2 and R 5 are both H. More preferably, R 1 is F, R 2 is H, R 4 is Cl and R 5 is H.
  • R 1 is F; R 2 is H; R 3 is an optionally substituted pyridinyl group; R 4 is Cl or CF 3 ; and R 5 is H. More preferably, R 1 is F; R 2 is H; R 3 is an optionally substituted pyridinyl group; R 4 is Cl; and R 5 is H.
  • R 3 is: wherein: R 17 is selected from H, alkyl, CN, haloalkyl, NHCO-alkyl, NR 13 R 13 ', alkoxy, SO 2 -alkyl, halo, O-(CH 2 )q-heterocycloalkyl, alkoxy-alkoxy, alkylamino-alkoxy, dialkylamino-alkoxy, alkoxyalkyl, haloalkoxy and O-(CH 2 ) P -cycloalkyl, wherein the cycloalkyl group is optionally substituted by one or more halo, alkyl or alkoxy groups; R 15 is selected from H and halo; R 19 is selected from H, alkoxy and alkoxy-alkyl; and R 20 is selected from H, halo and CO 2 R 16 .
  • R 1 and R 4 are selected from halo and haloalkyl (more preferably halo) and R 2 and R 5 are both H. More preferably, R 1 is F, R 2 is H, R 4 is Cl and R 5 is H.
  • R 17 is selected from H, alkyl, CN, haloalkyl, NHCO-alkyl, NR 13 R 13 ', alkoxy, SO 2 -alkyl, halo, O-(CH 2 )q-heterocycloalkyl, alkoxy-alkoxy, alkoxy-alkyl, haloalkoxy and O-(CH 2 ) P -cycloalkyl, wherein the cycloalkyl group is optionally substituted by one or more halo, alkyl or alkoxy groups
  • R 17 is selected from H, alkyl, CN, haloalkyl, NHCO-alkyl, NR 13 R 13 ', alkoxy, SO 2 -alkyl, halo, O-heterocycloalkyl, alkoxy-alkoxy, alkoxy-alkyl, haloalkoxy and O-cycloalkyl, wherein the cycloalkyl group is optionally substituted by one or more halo, alkyl or alkoxy groups.
  • R 17 is selected from haloalkyl and haloalkoxy, more preferably fluoroalkyl and fluoroalkoxy.
  • R 17 is selected from -O-CH 2 CF 3 , -O-CH 2 CH 2 CF 3 and -OCHF 2 , -OCH 2 CHF 2 .
  • R 17 is selected from fluoroalkyl, fluoroalkoxy, methylamino- alkoxy, dimethylamino-alkoxy, (piperidin-1 -yl)-alkoxy, O-(CH 2 ) P -cyclopropyl, O-(CH 2 ) P - cyclobutyl, wherein said cyclopropyl and cyclobutyl group is optionally substituted by an alkoxy group; and R 15 , R 19 and R 20 are all H.
  • R 17 is selected from CF 3 , -O-CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -OCHF 2 , -OCH 2 CHF 2 , -OCH 2 CH 2 NHMe, -OCH 2 CH 2 NHMe, (piperidin-1-yl)-CH 2 CH 2 -O-, -O- cyclopropyl, -O-CH 2 -cyclopropyl, methoxycyclobutyl-O-; and R 15 , R 19 and R 20 are all H.
  • R 17 is selected from H, alkoxy, SO 2 -alkyl, halo, O-cycloalkyl, O-heterocycloalkyl and haloalkoxy
  • R 15 is selected from H and halo
  • R 19 is selected from H, alkoxy and alkoxy-alkyl
  • R 20 is selected from H, halo and CO 2 R 16 .
  • R 17 is selected from H, OMe, OEt, O'Pr, F, SO 2 Me, halo, O- cyclobutyl, O-oxetanyl, and O-CH 2 CF 3 ;
  • R 15 is selected from H and F;
  • R 19 is selected from H and MeOCH 2 -;
  • R 20 is selected from H, F and CO 2 Me;
  • R 1 is F;
  • R 2 is H;
  • R 4 is Cl or CF 3 ;
  • R 5 is H.
  • R 17 is selected from H, OMe, OEt, O'Pr, F, SO 2 Me, halo, O- cyclobutyl, O-oxetanyl, and O-CH 2 CF 3 ;
  • R 15 is selected from H and F;
  • R 19 is selected from H and MeOCH 2 -;
  • R 20 is selected from H, F and CO 2 Me;
  • R 1 is F;
  • R 2 is H;
  • R 4 is Cl or CF 3 ;
  • R 5 is H.
  • the compound is of formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein: R 1 , R 4 , and R 5 are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, and halo;
  • R 2 and R 3 are each independently selected from H, halo, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl and CO 2 -alkyl, wherein said aryl, heteroaryl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl and alkoxy; and
  • Z, Y, R a , R b , and R 6 are as defined above.
  • Z is CH.
  • At least one of R 1 , R 2 , R 3 , R 4 and R 5 is other than H.
  • one of R 1 , R 2 , R 3 , R 4 and R 5 is other than H. In one preferred embodiment, two of R 1 , R 2 , R 3 , R 4 and R 5 are other than H.
  • three of R 1 , R 2 , R 3 , R 4 and R 5 are other than H.
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, haloalkyl, haloalkoxy and CO 2 -alkyl.
  • the pyrazolyl is a 1/7-pyrazol-1-yl group.
  • the oxazolyl group is an oxazol-5-yl group.
  • the thiazolyl group is a thiazol-4-yl group.
  • R 2 is selected from H, F, Cl, Br, CN, Me, methoxy, OCF 3 , CF 3 , OCHF 2 , Ph, pyrazolyl and CO 2 Me, wherein said Ph and pyrazolyl groups are each optionally further substituted by one or more alkyl groups.
  • the pyrazolyl is a 1/7- pyrazol-1-yl group.
  • R 2 and R 3 are each independently selected from F, Cl, Br, I, CN, CC>2-alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy.
  • R 2 and R 3 are each independently selected from F, Cl, Br, I, CN, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy and CO 2 -alkyl, more preferably, Cl, Br, and CF 3 , even more preferably Cl and CF 3 .
  • R 2 and R 3 are each independently selected from F, Cl, Br, I, CN, and C 1 -C 6 haloalkyl.
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, CN, methoxy, and haloalkyl.
  • R 2 and R 3 are each independently selected from CN, Cl, Br, OCF 3 and CF 3 , and more preferably are each independently selected from Cl and CF 3 . In one preferred embodiment, R 2 and R 3 are each independently selected from Cl, Br, and CF 3 , and more preferably independently selected from Cl and CF 3 .
  • one of R 2 and R 3 is Cl and the other is O CF 3 or OCHF 2 .
  • one of R 2 and R 3 is Cl and the other is CO 2 Me.
  • R 2 and R 3 are both Cl, or one of R 2 and R 3 is Cl and the other is CF 3 .
  • R 2 and R 3 are both Cl.
  • one of R 2 and R 3 is Cl, and the other is CF 3 .
  • one of R 2 and R 3 is CN, and the other is CF 3 .
  • one of R 2 and R 3 is Br, and the other is CF 3 .
  • one of R 2 and R 3 is Cl, and the other is OCF 3 .
  • one of R 2 and R 3 is Cl, and the other is Br.
  • one of R 2 and R 3 is Cl and the other is selected from OCF 3 ,
  • R 1 , R 4 , and R 5 are each independently selected from H, alkyl, alkoxy, OH, F, Cl, Br, and I.
  • R 1 , R 4 , and R 5 are each independently selected from H, Me, OMe, OH, F, Cl, Br, and I.
  • R 1 , R 4 , and R 5 are each independently selected from H, F, Cl, Br, and I.
  • R 5 is selected from H, F, Me, MeO and Cl, and is preferably H or F, more preferably H.
  • R 5 is selected from H, F and Cl, and is preferably H or F, more preferably H.
  • R 5 is selected from H, F and CN, and is preferably H.
  • R 1 and R 4 are both H.
  • R 1 is H;
  • R 2 is selected from H, F, Cl, Br, CN, Me, methoxy, OCF 3 , CF 3 , OCHF 2 , Ph, pyrazolyl and CO 2 Me;
  • R 4 is H or CF 3 , more preferably H;
  • R 5 is selected from H, F, Me, MeO, Cl, OH and CN, and is preferably H or F, more preferably H.
  • one of R 2 and R 3 is selected from aryl, O-aryl and heteroaryl, each of which is optionally substituted, and the other of R 2 and R 3 is H, and R 1 , R 4 and R 5 are all H.
  • the compound is of formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein where n is 0 or 1 and X1-X 5 form a 5- or 6-membered heteroaromatic group containing at least one nitrogen atom, said heteroaromatic group being optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl, NHCO-aryl, -(CH 2 )q-O-heteroaryl, CONH- aryl, aryloxy-alkyl, O-aralkyl, and O-aryl, wherein said aryl, heteroaryl, heterocycloalkyl, wherein
  • the compound is of formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein where n is 0 or 1 and X1-X 5 form a 5- or 6- membered heteroaromatic group containing at least one nitrogen atom, said heteroaromatic group being optionally substituted by one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-aryl, O-heteroaryl, CONH-aryl, aryloxy-alkyl, O-aralkyl, and O-aryl, wherein said aryl, heteroaryl, heterocycloalkyl, O- cycloalkyl, NHCO-aryl, O-heteroaryl, CONH-aryl,
  • n is 0 or 1 and X1-X 5 form a 5- or 6-membered heteroaromatic group containing at least one nitrogen atom, said heteroaromatic group being optionally substituted by one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl and O-aryl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15
  • n is 0 or 1 and X1-X 5 form a 5- or 6-membered heteroaromatic group containing at least one nitrogen atom, said heteroaromatic group being optionally substituted by one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl and O-aryl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl, and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15
  • X 3 is CR 3 , wherein R 3 is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindolinyl, oxoindolinyl, imidazolyl, benzooxazinyl, pyrrolopyridinyl, oxotetrohydroisoquinolinyl, benzo[c][1 ,2,5]oxadiazolyl, or 2H-benzo[b][1 ,4]oxazin-3(4H)-onyl; each of which is optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR
  • X 1 is CR 1 and X 4 is CR 4 , wherein R 1 and R 4 are both H.
  • X 5 is CR 5 , wherein R 5 is selected from H, F, Me, MeO, Cl, OH and CN, and is preferably H or F, more preferably F.
  • X 2 is CR 2 , wherein R 2 is selected from Cl, Br, and CF 3 , more preferably Cl.
  • X 3 is CR 3
  • R 3 is as defined as for formula (la) above.
  • X 3 is CR 3 , wherein R 3 is selected from (a-1)-(a- 38) as described above, more preferably (a-1)-(a-28), even more preferably (a-1)-(a-16).
  • R 3 is selected from (a-1)-(a-16), each of which is optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl- heterocycloalkyl, alkyl-cycloalkyl, aryl, and heteroaryl, wherein R 13 , R 13 ', R 14 , R 14 ', R 15 , and R 15 ' are each independently selected from H, alkyl, and alkoxyalkyl.
  • the compound is of formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein where n is 0 or 1 and X1-X 5 form a 5- or 6-membered heteroaromatic group containing at least one nitrogen atom, said heteroaromatic group being optionally substituted by one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl and O-aryl; and Z, Y, R a , R b , and Re are as defined above.
  • Z is CH.
  • R 1 and R 4 are H.
  • n is 1
  • X1-X 5 form a 6-membered heteroaromatic group selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazinyl, 1 ,2,4,5-tetrazinyl and 1 ,2,3,4-tetrazinyl, each of which is optionally substituted by one or more substituents selected from halo, CN, alkoxy, alkyl, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O- heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O
  • n is 1
  • X1-X 5 form a 6-membered heteroaromatic group selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazinyl, 1 ,2,4,5-tetrazinyl and 1 ,2,3,4-tetrazinyl, each of which is optionally substituted by one or more substituents selected from halo, CN, alkoxy, alkyl, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O- heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O
  • the compound is of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 4 is N or CR 4 ; and R 1 , R 2 , R 3 and R 4 are each independently selected from H, halo, haloalkyl, alkyl, alkoxy, CN, aryl, heterocycloalkyl, heteroaryl and O-aryl, more preferably, H, halo, CN, alkoxyl, alkyl and haloalkyl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, (CH 2 )m-
  • R 13 , R 13 ', R 14 , R 14 ', R 15 , and R 15 ' are each independently selected from H, alkyl, and alkoxyalkyl.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, halo, haloalkyl, alkyl, alkoxy, CN, aryl, heterocycloalkyl, heteroaryl and O- aryl, more preferably, H, halo, CN, alkoxyl, alkyl and haloalkyl, wherein said aryl, heteroaryl, heterocycloalkyl, O-cycloalkyl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR ⁇ R ⁇ ', heterocycloalkyl, alkyl- heterocycloalkyl, alkyl-cycloalkyl, aryl, and heteroaryl.
  • R 3 is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, indazolyl, triazolyl, benzotriazolyl, oxoisoindolinyl, oxoindolinyl, imidazolyl, benzooxazinyl, pyrrolopyridinyl, oxotetrohydroisoquinolinyl, benzo[c][1 ,2,5]oxadiazolyl, or 2H-benzo[b][1 ,4]oxazin-3(4H)-onyl; each of which is optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 - alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl-NR ⁇ R ⁇ ', heterocycloalkyl
  • X 2 is CR 2 , wherein R 2 is selected from Cl, Br, and CF 3 , more preferably Cl.
  • R 3 is as defined as for formula (la) above.
  • X 3 is CR 3 , wherein R 3 is selected from (a-1)-(a- 38) as described above, more preferably (a-1) to (a-28), more preferably (a-1)-(a-16).
  • R 3 is selected from (a-1) to (a-28) each of which is optionally further substituted by one or more groups independently selected from halo, alkyl, alkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, CN, hydroxyalkyl, CONR 14 R 14 ', alkyl- NR 15 R 15 ', heterocycloalkyl, alkyl-heterocycloalkyl, alkyl-cycloalkyl, aryl, and heteroaryl, wherein R 13 , R 13 ', R 14 , R 14 ', R 15 , and R 15 ' are each independently selected from H, alkyl, and alkoxyalkyl.
  • the compound is of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 4 is N or CR 4 ; and R 1 , R 2 , R 3 and R 4 are each independently selected from H, halo, haloalkyl, alkyl, alkoxy, CN, aryl, heteroaryl and O-aryl, more preferably, H, halo, CN, alkoxyl, alkyl and haloalkyl; and
  • Z, Y, R a , R b , and Re are as defined above.
  • Z is CH.
  • R 1 and R 4 are H.
  • R 3 is selected from halo and haloalkyl, and is more preferably selected from Cl, F and CF 3 .
  • the compound is of formula (Ic), wherein X 1 is N or CR 1 , X 2 is N or CR 2 and X 4 is CR 4 . In one preferred embodiment, the compound is of formula (Ic), wherein X 1 is CR 1 , X 2 is CR 2 , and X 4 is CR 4 .
  • R 3 is selected from halo, haloalkyl, alkyl, alkoxy and CN. Even more preferably, R 3 is selected from halo and haloalkyl. More preferably still, R 3 is selected from Cl, F and CF 3 , even more preferably, Cl and CF 3 .
  • R 1 , R 2 and R 4 are each independently selected from H and halo, more preferably, H and Cl. More preferably, at least one of R 2 and R 4 is halo.
  • X 3 is CR 3 , where R 3 is selected from halo, haloalkyl, alkyl, alkoxy and CN;
  • X 1 is CR 1 , where R 1 is H;
  • X 2 is CR 2 , where R 2 is selected from H, halo, haloalkyl, alkyl, alkoxy and CN;
  • X 4 is CR 4 , where R 4 is selected from H, halo, haloalkyl, alkyl, alkoxy and CN; wherein at least one of R 2 and R 4 is other than H.
  • X 3 is CR 3 , where R 3 is selected from halo and haloalkyl
  • X 1 is CR 1 , where R 1 is H;
  • X 2 is CR 2 , where R 2 is selected from H, halo and haloalkyl;
  • X 4 is CR 4 , where R 4 is selected from H, halo and haloalkyl; wherein at least one of R 2 and R 4 is other than H.
  • X 3 is CR 3 , where R 3 is selected from halo and haloalkyl
  • X 1 is CR 1 , where R 1 is H;
  • X 2 is CR 2 , where R 2 is selected from halo and haloalkyl
  • X 4 is CR 4 , where R 4 is H.
  • X 3 is CR 3 , where R 3 is selected from halo and haloalkyl
  • X 1 is CR 1 , where R 1 is H;
  • X 2 is CR 2 , where R 2 is H;
  • X 4 is CR 4 , where R 4 is selected from halo and haloalkyl.
  • X 3 is CR 3 , where R 3 is selected from Cl, F and CF 3 , even more preferably, Cl and CF 3 ;
  • X 1 is CR 1 , where R 1 is H;
  • X 2 is CR 2 , where R 2 is selected from H and Cl;
  • X 4 is CR 4 , where R 4 is selected from H and Cl; wherein at least one of R 2 and R 4 is other than H.
  • X 3 is CR 3 , where R 3 is selected from Cl, F and CF 3 , even more preferably, Cl and CF 3 ;
  • X 1 is CR 1 , where R 1 is H;
  • X 2 is CR 2 , where R 2 is Cl;
  • X 4 is CR 4 , where R 4 is H.
  • X 3 is CR 3 , where R 3 is selected from Cl, F and CF 3 , even more preferably, Cl and CF 3 ;
  • X 1 is CR 1 , where R 1 is H;
  • X 2 is CR 2 , where R 2 is H;
  • X 4 is CR 4 , where R 4 is Cl.
  • X 4 is N
  • X 1 is CR 1
  • X 2 is CR 2
  • R 1 and R 2 are each independently selected from H and halo, more preferably, H and Cl.
  • X 1 is N
  • X 2 is CR 2
  • X 4 is CR 4 .
  • R 2 and R 4 are both H.
  • X 2 is N
  • X 1 is CR 1
  • X 4 is CR 4
  • R 1 and R 4 are each independently selected from H and halo, more preferably, H and Cl.
  • the compound is of formula (lb) wherein n is 0, and X1-X 4 form a 5-membered heteroaromatic group containing at least one nitrogen atom, said heteroaromatic group being optionally substituted by one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl and O-aryl.
  • the compound is of formula (lb) wherein n is 0, and X1-X 4 form a 5-membered heteroaromatic group selected from oxadiazoyl, thiadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, diazolyl, triazolyl, isoxazolyl, isothiazolyl, tetrazolyl, oxazolyl, and thiazolyl, and wherein said heteroaromatic group is optionally substituted by one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O- cycloalkyl and O-aryl.
  • the compound is of formula (lb) wherein n is 0, and X1-X 4 form a 5-membered heteroaromatic group selected 1/7-imidazol-5-yl, 1/7-imidazol-4-yl, 1/7- imidazol-2-yl, 1/7-pyrrol-2-yl, 1/7-pyrrol-3-yl, 1/7-pyrrol-4-yl, 1/7-pyrazol-5-yl, 1/7-pyrazol-3-yl, 1/7-pyrazol-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1 /7-1 ,2,4-triazol-3-yl, 1 /7-1 ,2,4-triazol- 5-yl, 1/7-1 ,2,3-triazol-4-yl, 1/7-1 ,2,3-triazol-5-yl, thiazol-5-yl, thiazol-4-yl, thiazol-5-
  • the 5-membered heteroaromatic group is selected from 1 ,2,4-oxadiazol-3-yl, 1 ,2,5-oxadiazol-3-yl and 1 ,3,4-thiadiazol-2-yl, each of which is optionally substituted by one or more substituents selected from alkyl, halo, CN, alkoxy and haloalkyl.
  • the compound is of formula (Id), or a pharmaceutically acceptable salt or solvate thereof,
  • X1-X 4 form a heteroaromatic group containing at least one nitrogen atom, wherein:
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 3 is N, O, or CR 3 ;
  • X 4 is selected from NR 15 " , O and S, where R 15 " is H, alkyl or haloalkyl; and R 1 -R 3 are each independently selected from H, halo, CN, alkoxyl, alkyl, haloalkyl, aryl, heteroaryl and O-aryl, more preferably, H, halo, CN, alkoxyl, alkyl and haloalkyl; and
  • the compound is of formula (Id), wherein X 1 is N, X 2 is N, X 3 is CR 3 and X 4 is S.
  • Z is CH.
  • the compound is of formula (Ih), or a pharmaceutically acceptable salt or solvate thereof, wherein: X1-X 4 form a heteroaromatic group containing at least one nitrogen atom, wherein:
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 3 is selected from NR 15 “ , O and S, where R 15 " is H, alkyl or haloalkyl;
  • X 4 is N or CR 4 ; and R 1 , R 2 and R 4 are each independently selected from H, halo, CN, alkoxyl, alkyl, haloalkyl, aryl, heteroaryl and O-aryl, more preferably, H, halo, CN, alkoxyl, alkyl and haloalkyl.
  • the compound is of formula (Ih), wherein X 1 is CR 1 , X 2 is N, X 3 is O and X 4 is N; or X 1 is N, X 2 is CR 2 , X 3 is O and X 4 is N.
  • ring B is an optionally substituted bicyclic heteroaromatic group containing at least one nitrogen atom, preferably, an optionally substituted 9- or 10- membered bicyclic heteroaromatic group containing at least one nitrogen atom.
  • ring B is a bicyclic heteroaromatic group selected from benzimidazolyl, pyrazolopyridinyl, indolyl, indolizinyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl and naphthyridinyl, and wherein said bicyclic heteroaromatic group is optionally substituted by one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl and O-aryl.
  • B is a quinolin-6-yl group or a 2H-pyrazolo[3,4- c]pyridin-5-yl group, each of which is optionally substituted by one or more substituents selected from halo, CN, alkyl, alkoxy and haloalkyl.
  • the compound is of formula (li), or a pharmaceutically acceptable salt or solvate thereof, wherein X 2 and X 3 are both C, one, two or three of X 1 , X 4 , X 5 -X9 are N and the rest are selected from C-H, C-alkyl and C-haloalkyl, wherein Y,Z, Re, R a , R b are as defined above.
  • Preferred definitions for R 3 , R a , R b , Y and Z as defined above apply equally to compounds of formula (li).
  • the compound is of formula (li), wherein X 9 is N, X 2 and X 3 are both C, X 1 , X 4 , X 5 X 6 and X 7 are CH, and X 8 is C-haloalkyl more preferably, CF 3 .
  • B is a bicyclic heteroaromatic group containing at least one nitrogen atom which is selected from the following: wherein:
  • X 2 and X 3 are both C;
  • X 7 is selected from O, S and NR 15 " , where R 15 " is H, alkyl or haloalkyl; and one, two or three of X 1 , X 4 , X 5 , X 6 and X 8 are N and the rest are selected from C-H, C-alkyl and C-haloalkyl.
  • B is a heteroaromatic group containing at least one nitrogen atom which is of formula: wherein X 5 , X 8 are N, X 2 and X 3 are both C, X 1 , X 4 , X 5 and X 6 are CH, and X 7 is N-haloalkyl, more preferably N-CHF 2 .
  • ring B is preferably selected from the following groups:
  • ring B is selected from groups (i)-(xxviii) above.
  • ring B is selected from groups (i)-(xxviii) above, Z is CH, R a , R b and R 6 are H, and Y is CH 2 .
  • ring B is: wherein R 3 is selected from:
  • ring B is selected from the groups listed above, Z is CH, R a , R b and Re are H, and Y is CH 2 . wherein B, Y, R a , R b , Z and Re are as defined above.
  • the compound is in enantiomerically pure form. In one preferred embodiment, the compound is in the form of a mixture that is enantiomerically enriched with a compound of formula (1.1).
  • the compound is of formula (1.2): wherein B, Y, R a , R b , Z and Re are as defined above.
  • the compound is in enantiomerically pure form. In one preferred embodiment, the compound is in the form of a mixture that is enantiomerically enriched with a compound of formula (1.2).
  • the compound is in the form of a mixture comprising a compound of formula (1.1) and its corresponding enantiomer of formula (1.2).
  • the mixture is a racemic mixture, i.e. a 50:50 mixture of a compound of formula (1.1) and its corresponding enantiomer of formula (1.2).
  • Racemic mixtures can be used to prepare enantiomerically pure compounds of formula (1.1) or (1.2) by separating the compounds of formula (1.1) or (1.2) by standard methods, for example by chemical resolution using optically active acid or by the use of column chromatography or reverse-phase column chromatography using a substantially optically active (or "chiral ") stationary phase as known to those skilled in the art. Racemic mixtures can also be used to prepare enantiomerically enriched mixtures of compounds of formula (1.1) or (1.2). Mixtures enriched with either a compound of formula (1.1) or (1.2) can also be obtained from the appropriate enantiomerically enriched precursors.
  • the compound is in the form of a mixture comprising enantiomers wherein the weightweight ratio is at least approximately 2:1 or greater, preferably at least approximately 5:1 or greater, most preferably at least approximately 10:1 or greater in favour of the enantiomer that displays significant in vitro and/or in vivo activity (the eutomer).
  • the compound is in the form of a mixture comprising a compound of formula (1.1) and its corresponding enantiomer of formula (1.2), wherein the weightweight ratio of said compound of formula (1.1) to said compound of formula (1.2) is greater than 1.05:1, more preferably, greater than 2:1 , even more preferably greater than 5:1, even more preferably greater than 10:1.
  • the compound is in the form of a mixture comprising a compound of formula (1.1) and its corresponding enantiomer of formula (1.2), which is substantially enriched with said compound of formula (1.1).
  • the compound is in the form of a mixture comprising a compound of formula (1.1) and its corresponding enantiomer of formula (1.2), wherein the weightweight ratio of said compound of formula (1.2) to said compound of formula (1.1) is greater than 1.05:1 , more preferably, greater than 2:1, even more preferably greater than 5:1, even more preferably greater than 10:1.
  • the compound is in the form of a mixture comprising a compound of formula (1.1) and its corresponding enantiomer of formula (1.2), which is substantially enriched with said compound of formula (1.2).
  • the compound is selected from the following:
  • Another aspect of the invention relates to a compound of formula (If), or a pharmaceutically acceptable salt or solvate thereof, wherein: R 11 is selected from H, alkyl, haloalkyl, halo, OH and O-alkyl; and
  • ring B is: a monocyclic aromatic group; or a monocyclic or bicyclic heteroaromatic group, each of which is optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO 2 -alkyl, wherein said aryl, heteroaryl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl and alkoxy;
  • Z is CR 12 ;
  • Y is CR 10 R 10 ', wherein R 10 and R 10 ' are each independently selected from H, F, alkyl, and haloalkyl; R a and R b are each independently selected from H and alkyl; and R 11 and R 12 are each independently selected from H, alkyl, haloalkyl, halo, OH and O-alkyl.
  • R 11 is selected from H, alkyl, haloalkyl, halo and O-alkyl.
  • R 11 is OH.
  • R 12 is selected from H, CF 3 , Me, Cl, F, Br, OH and OMe.
  • R 12 is H, i.e. Z is CH.
  • Another aspect of the invention relates to a compound of formula (Ij) or a pharmaceutically acceptable salt or solvate thereof,
  • ring A is selected from:
  • Y is CR 10 R 10 ', wherein R 10 and R 10 ' are each independently selected from H, F, alkyl, and haloalkyl; preferably Y is CH 2 ; R a and R b are each independently selected from H and alkyl; preferably R a and R b are both H; R 1 ', R 2 ', R 4 ' and R 5 ' are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH and halo; R 3 ' is a pyridinyl group substituted by one or more substituents selected from CN, haloalkyl, haloalkoxy, NHCO-alkyl, NR 13 R 13 ', SO 2 -alkyl, O-(CH 2 ) q -heterocycloalkyl, alkoxy-alkoxy, alkylamino-alkoxy, dialkylamino-alkoxy, alkoxy-alkyl and
  • Re' is H or alkyl, more preferably H;
  • R7, R 3 and Rg are each independently selected from H, halo and alkyl; R 13 and R 13 ' are each independently selected from H, alkyl, and alkoxy-alkyl; and p and q are each independently 0 to 3.
  • p and q are each independently 0 or 1.
  • R 1 ' and R 4 ' are both halo.
  • R 1 ' and R 4 ' are selected from Cl and F.
  • R 1 ' is F and R 4 ' is Cl.
  • ring A is selected from: Y is CH 2 ; R a and R b are both H; R 1 ' is F and R 4 ' is Cl; and R 1 7' is selected from haloalkyl, haloalkoxy, alkylamino-alkoxy, dialkylamino-alkoxy, O- (CH 2 )q-heterocycloalkyl, O-(CH 2 ) P -cycloalkyl, wherein said cycloalkyl group is optionally substituted by one or more alkoxy groups; p is 0 or 1 ; q is 0 or 1 ; and R 15 ', R 1 9' and R 20 ' are all H.
  • ring A is:
  • ring A is:
  • R 1 7' is selected from haloalkyl and haloalkoxy, more preferably fluoroalkyl and fluoroalkoxy.
  • R 1 7' is selected from -O-CH 2 CF 3 , -O-CH 2 CH 2 CF 3 and -OCHF 2 , -OCH 2 CHF 2 .
  • R 1 7' is selected from fluoroalkyl, fluoroalkoxy, methylaminoalkoxy, dimethylamino-alkoxy, (piperidin-l-yl)-alkoxy, O-(CH 2 ) P -cyclopropyl, O-(CH 2 ) P - cyclobutyl, wherein said cyclopropyl and cyclobutyl group is optionally substituted by an alkoxy group; and R 15 ', R 19 ' and R 20 ' are all H.
  • R 1 7' is selected from CF 3 , -O-CH 2 CF 3 , -O-CH 2 CH 2 CF 3 , -OCHF 2 , -OCH 2 CHF 2 , -OCH 2 CH 2 NHMe, -OCH 2 CH 2 NHMe, (piperidin-1-yl)-CH 2 CH 2 -O-, -O- cyclopropyl, -O-CH 2 -cyclopropyl, methoxycyclobutyl-O-; and R 15 ', R 19 ' and R 20 ' are all H.
  • the compound of formula (Ij) is selected from compounds 220, 222, 223, 239, 240, 241, 300, 301 , 309, 312, 317, 321 , 322, 324, 325, 332 and 334 described herein.
  • a further aspect of the invention relates to a compound selected from the following: and enantiomers thereof, and mixtures of enantiomers thereof, including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof.
  • the compound of the invention is selected from the following: and enantiomers thereof, and mixtures of enantiomers thereof, including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof.
  • the compound is selected from the following: 1-28, 31, 32, 35, 37-39, 41-44, 46-49, 51-53, 55-60, 63-89, 91-93, 96-118, 120-141, 143-150, 152-157, 159-173, 175-286, and 289-343.
  • the compound is selected from the following: 1-11 , 15-20, 20, 22-24, 26, 28, 31, 32, 35, 37, 39, 41, 42, 44, 46, 47, 49, 51, 52, 55, 59, 60, 63-67, 69, 70, 74-77, 79, 81 , 82, 84-87, 92, 96-98, 100-105, 108-115, 120, 121, 123-127, 131 , 132, 134, 136, 138, 139, 141 , 144, 145, 147, 152-155, 157, 159, 162-173, 175-178, 182-185, 188-191 , 193-195, 197-202, 205-223, 225-227, 229, 230, 232-235, 237-270, 272-279, 281,
  • a further aspect of the invention relates to a process for preparing a compound of formula (le) as defined above, where Y is CH 2 , and R a , R b and Re are H, said process comprising the steps of: (i) treating a compound of formula 1-1 a with glyoxylic acid monohydrate to give a compound of formula 1-1 b;
  • the compound of formula 1-1 c is prepared by a process comprising the steps of:
  • a further aspect of the invention relates to a process for preparing a compound of formula (la) as defined above where R 3 is an optionally substituted heteroaryl ( "Het "), said process comprising the step of coupling a heteroaryl boronic acid with a bromophenyl intermediate as shown below:
  • XPhos dicyclohexyl[2',4',6'-tris(propan-2-yl)[1 ,T- biphenyl]-2-yl]phosphane.
  • Compounds which bear a pyrimidin-2(1/7)-one group fused to the bicyclic nitrogencontaining core can be prepared by a process comprising the following steps: (i) reacting a compound of formula l-3a with 1 ,1-dimethoxy-N, N- dimethylmethanamine to form a compound of formula l-3b; (ii) treating said compound of formula l-3b with sodium ethoxide/urea to form a compound of formula l-3c;
  • a further aspect of the invention relates to compounds as described herein for use in medicine.
  • the compounds have particular use in the field of oncology, immuno-oncology, and immunology as described in more detail below.
  • the compound of the invention modulates GPR65, and more preferably inhibits GPR65 signalling.
  • Yet another aspect of the invention relates to compounds as described herein for use as a medicament, preferably for use in treating or preventing a disorder selected from a proliferative disorder and an immune disorder.
  • Another aspect of the invention relates to compounds as described herein for use in treating or preventing asthma and/or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • GPR65 variant/SNP rs6574978
  • rs6574978 has been shown to be associated with asthma/COPD syndrome with almost GWAS significant p value (1.18x10e-7) (Hardin, 2014).
  • GPR65 activation by pH pH is low/acidic in asthmatic lungs
  • GPR65 KO mice have attenuated asthma symptoms (Kottyan, 2009).
  • ARDS acute respiratory distress syndrome
  • GPR65 has been shown to be protective in a model of LPS-induced acute lung injury model (Tsurumaki, 2015).
  • One aspect of the invention relates to a compound as described herein for use in treating a proliferative disorder.
  • the proliferative disorder is a cancer or leukemia.
  • the cancer is a solid tumour and/or metastases thereof.
  • the cancer is selected from melanoma, renal cell carcinoma (RCC), gastric cancer, acute myeloid leukaemia (AML), triple negative breast cancer (TNBC), colorectal cancer, head and neck cancer, colorectal adenocarcinoma, pancreatic adenocarcinoma, lung cancer, sarcoma, ovarian cancer, and gliomas, preferably glioblastoma (GBM).
  • RCC renal cell carcinoma
  • AML acute myeloid leukaemia
  • TNBC triple negative breast cancer
  • colorectal cancer head and neck cancer
  • colorectal adenocarcinoma pancreatic adenocarcinoma
  • lung cancer sarcoma
  • ovarian cancer preferably glioblastoma (GBM).
  • GBM glioblastoma
  • GPR65 modulators are capable of preventing the increase in cytoplasmic cAMP in tumour-associated macrophages (TAMs), natural killer (NK) cells and subsets of T cells that would typically result from their exposure to the acidic tumour microenvironment and concomitant GPR65 activation.
  • TAMs tumour-associated macrophages
  • NK natural killer cells
  • This reduction in the level of cytoplasmic cAMP in turn reduces the levels of ICER and pro- inflammatory mediators such as CXCL10 and TNFa, preventing the polarization of TAMs and alteration of other immune cells that are associated with a non-inflam matory and tumour-permissive environment.
  • GPR65 modulators are expected to result in an increase in the visibility of the tumour to the immune system leading to increased immune- mediated tumour clearance. This suggests that modulation of GPR65 activity could be an effective treatment for cancer as stand-alone therapy or in combination with cancer immunotherapies (vaccines, agents that promote T cell mediated immune responses) or in patients that do not respond to immunomodulatory approaches such as PD1/PDL-1 blockade.
  • Another aspect of the invention relates to a compound as described herein for use in treating or preventing an immune disorder, preferably an autoimmune disease.
  • the autoimmune disease is selected from psoriasis, psoriatic arthritis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), autoimmune thyroiditis (Hashimoto's thyroiditis), Graves' disease, uveitis (including intermediate uveitis), ulcerative colitis, Crohn's disease, autoimmune uveoretinitis, systemic vasculitis, polymyositis-dermatomyositis, systemic sclerosis (scleroderma), Sjogren's Syndrome, ankylosing spondylitis and related spondyloarthropathies, sarcoidosis, autoimmune hemolytic anemia, immunological platelet disorders, autoimmune polyendocrinopathies, autoimmune myocarditis, type I diabetes and atopic dermatitis.
  • RA rheumatoid arthritis
  • MS multiple sclerosis
  • SLE systemic
  • the autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and multiple sclerosis (MS).
  • GPR65 modulators will prevent the upregulation of ICER in CD4+ T cells. This, in turn, is expected to prevent the ICER- associated suppression of IL-2 that biases CD4+ T cells toward the inflammatory Th17 phenotype associated with increased pathogenicity in the context of autoimmune disease. This is supported by the fact that mutations in the GPR65 locus are associated with several autoimmune diseases, such as multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, and Crohn's disease (Gaublomme, 2015). This suggests that modulation of GPR65 activity could be an effective treatment for autoimmune diseases.
  • Another aspect relates to a compound as described herein for use in treating or preventing a disorder caused by, associated with or accompanied by abnormal activity against GPR65.
  • Another aspect relates to a compound as described herein for use in treating or preventing a GPR65-associated disease or disorder.
  • Another aspect of the invention relates to a method of treating a disorder as described above comprising administering a compound as described herein to a subject.
  • Another aspect of the invention relates to a method of treating a GPR65-associated disease or disorder in a subject.
  • the method according to this aspect of the present invention is effected by administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, as described hereinabove, either perse, or, more preferably, as a part of a pharmaceutical composition, mixed with, for example, a pharmaceutically acceptable carrier, as is detailed hereinafter.
  • Yet another aspect of the invention relates to a method of treating a subject having a disease state alleviated by modulation of GPR65 wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to the invention.
  • Another aspect relates to a method of treating a disease state alleviated by modulation of GPR65, wherein the method comprises administering to a subject a therapeutically effective amount of a compound according to the invention.
  • the subject is a mammal, more preferably a human.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a disease or disorder, substantially ameliorating clinical symptoms of a disease or disorder or substantially preventing the appearance of clinical symptoms of a disease or disorder.
  • preventing refers to a method for barring an organism from acquiring a disorder or disease in the first place.
  • terapéuticaally effective amount refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated.
  • a therapeutically effective amount can be estimated initially from cell culture assays.
  • a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50 or the IC100 as determined in cell culture. Such information can be used to more accurately to determine useful doses in humans.
  • Initial dosages can also be estimated from in vivo data. Using these initial guidelines one of ordinary skill in the art could determine an effective dosage in humans.
  • toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD 50 and the ED 50 .
  • the dose ratio between toxic and therapeutic effect is the therapeutic index and can be expressed as the ratio between LD 50 and ED 50 .
  • Compounds which exhibit high therapeutic indices are preferred.
  • the data obtained from these cell cultures assays and animal studies can be used in formulating a dosage range that is not toxic for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see, e.g., Fingl et al, 1975, The Pharmacological Basis of Therapeutics, chapter 1 , page 1).
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active compound which are sufficient to maintain therapeutic effect.
  • Usual patient dosages for oral administration range from about 50-2000 mg/day, commonly from about 100-1000 mg/day, preferably from about 150-700 mg/day and most preferably from about 250-500 mg/day or from 50-100 mg/day.
  • therapeutically effective serum levels will be achieved by administering multiple doses each day.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • One skilled in the art will be able to optimize therapeutically effective local dosages without undue experimentation.
  • GPR65-related disease or disorder refers to a disease or disorder characterized by inappropriate GPR65 activity.
  • Inappropriate GPR65 activity refers to either an increase or decrease in GPR65 activity as measured by enzyme or cellular assays, for example, compared to the activity in a healthy subject. Inappropriate activity could also be due to overexpression of GPR65 in diseased tissue compared with healthy adjacent tissue.
  • Preferred diseases or disorders that the compounds described herein may be useful in preventing include proliferative disorders and immune disorders as described hereinbefore, as well as asthma and chronic obstructive pulmonary disease.
  • the present invention further provides use of compounds as defined herein in the preparation of a medicament for the treatment of a disease where it is desirable to modulate GPR65.
  • diseases include proliferative disorders and immune disorders as described hereinbefore, as well as asthma and chronic obstructive pulmonary disease.
  • preparation of a medicament includes the use of the components of the invention directly as the medicament in addition to their use in any stage of the preparation of such a medicament.
  • the compound prevents the increase in cytoplasmic cAMP levels expected following GPR65 activation at acidic pH. This prevention of cAMP accumulation in turn prevents downstream signalling through ICER, as described above.
  • the "Human GPR65 cyclic adenosine monophosphate (cAMP) Homogeneous Time Resolved Fluorescence (HTRF) antagonist assay”, or simply “cAMP assay”, as described in the accompanying examples, can be used to measure the potency of GPR65 modulators, which is expressed as the concentration of compound required to reduce the increase in cAMP concentration upon GPR65 activation by 50% (i.e. an IC50).
  • the compound exhibits an IC50 value in the cAMP assay of less than about 25 pM. More preferably, the compound exhibits an IC50 value in the cAMP assay of less than about 10 pM, more preferably, less than about 5 pM, even more preferably, less than about 1 pM, even more preferably, less than about 0.1 pM.
  • the compound exhibits an hGPR65 IC50 value of less than ⁇ 5 pM, more preferably less than ⁇ 500 nM in the aforementioned assay.
  • the compound, or compound for use, according to the invention exhibits an IC50 of > 500 nM and ⁇ 5 pM in a Human GPR65 cyclic adenosine monophosphate (cAMP) Homogeneous Time Resolved Fluorescence (HTRF) antagonist assay as described in the accompanying examples.
  • the compound is selected from those denoted "high " or "medium " in Table 1.
  • the compound, or compound for use, according to the invention exhibits an IC50 of ⁇ 500 nM in a Human GPR65 cAMP HTRF antagonist assay as described in the accompanying examples.
  • the compound is selected from those denoted "high " in Table 1.
  • the compounds or physiologically acceptable salt, ester or other physiologically functional derivative thereof, described herein may be presented as a pharmaceutical formulation, comprising the compounds or physiologically acceptable salt, ester or other physiologically functional derivative thereof, together with one or more pharmaceutically acceptable carriers, excipients or diluents therefor and optionally other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the pharmaceutical compositions may be for human or animal usage in human and veterinary medicine.
  • suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like.
  • suitable diluents include ethanol, glycerol and water.
  • compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s), buffer(s), flavouring agent(s), surface active agent(s), thickener(s), preservative(s) (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • suitable binder(s) lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s), buffer(s), flavouring agent(s), surface active agent(s), thickener(s), preservative(s) (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • Suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol.
  • Suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • compositions include those suitable for oral, topical (including dermal, buccal and sublingual), rectal or parenteral (including subcutaneous, intradermal, intramuscular and intravenous), nasal and pulmonary administration e.g., by inhalation.
  • the formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Pharmaceutical formulations suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of active compound.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent.
  • Moulded tablets may be made by moulding an active compound with an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored.
  • Capsules may be prepared by filling an active compound, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner.
  • Cachets are analogous to capsules wherein an active compound together with any accessory ingredient(s) is sealed in a rice paper envelope.
  • An active compound may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged, e.g., in a sachet.
  • Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.
  • Formulations for oral administration include controlled release dosage forms, e.g., tablets wherein an active compound is formulated in an appropriate release - controlling matrix, or is coated with a suitable release - controlling film. Such formulations may be particularly convenient for prophylactic use.
  • compositions suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories.
  • Suitable carriers include cocoa butter and other materials commonly used in the art.
  • the suppositories may be conveniently formed by admixture of an active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of an active compound in aqueous or oleaginous vehicles.
  • Injectable preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers which are sealed after introduction of the formulation until required for use.
  • an active compound may be in powder form which is constituted with a suitable vehicle, such as sterile, pyrogen-free water, before use.
  • An active compound may also be formulated as long-acting depot preparations, which may be administered by intramuscular injection or by implantation, e.g., subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins. Such long-acting formulations are particularly convenient for prophylactic use.
  • Formulations suitable for pulmonary administration via the buccal cavity are presented such that particles containing an active compound and desirably having a diameter in the range of 0.5 to 7 microns are delivered in the bronchial tree of the recipient.
  • such formulations are in the form of finely comminuted powders which may conveniently be presented either in a pierceable capsule, suitably of, for example, gelatin, for use in an inhalation device, or alternatively as a self-propelling formulation comprising an active compound, a suitable liquid or gaseous propellant and optionally other ingredients such as a surfactant and/or a solid diluent.
  • suitable liquid propellants include propane and the chlorofluorocarbons
  • suitable gaseous propellants include carbon dioxide.
  • Self-propelling formulations may also be employed wherein an active compound is dispensed in the form of droplets of solution or suspension.
  • Such self-propelling formulations are analogous to those known in the art and may be prepared by established procedures. Suitably they are presented in a container provided with either a manually-operable or automatically functioning valve having the desired spray characteristics; advantageously the valve is of a metered type delivering a fixed volume, for example, 25 to 100 microlitres, upon each operation thereof.
  • an active compound may be in the form of a solution or suspension for use in an atomizer or nebuliser whereby an accelerated airstream or ultrasonic agitation is employed to produce a fine droplet mist for inhalation.
  • Formulations suitable for nasal administration include preparations generally similar to those described above for pulmonary administration. When dispensed such formulations should desirably have a particle diameter in the range 10 to 200 microns to enable retention in the nasal cavity; this may be achieved by, as appropriate, use of a powder of a suitable particle size or choice of an appropriate valve. Other suitable formulations include coarse powders having a particle diameter in the range 20 to 500 microns, for administration by rapid inhalation through the nasal passage from a container held close up to the nose, and nasal drops comprising 0.2 to 5% w/v of an active compound in aqueous or oily solution or suspension.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
  • Formulations suitable for topical formulation may be provided for example as gels, creams or ointments. Such preparations may be applied e.g. to a wound or ulcer either directly spread upon the surface of the wound or ulcer or carried on a suitable support such as a bandage, gauze, mesh or the like which may be applied to and over the area to be treated.
  • a suitable support such as a bandage, gauze, mesh or the like which may be applied to and over the area to be treated.
  • Liquid or powder formulations may also be provided which can be sprayed or sprinkled directly onto the site to be treated, e.g. a wound or ulcer.
  • a carrier such as a bandage, gauze, mesh or the like can be sprayed or sprinkle with the formulation and then applied to the site to be treated.
  • a process for the preparation of a pharmaceutical or veterinary composition as described above comprising bringing the active compound(s) into association with the carrier, for example by admixture.
  • the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • the invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound as described herein into conjunction or association with a pharmaceutically or veterinarily acceptable carrier or vehicle.
  • the compounds of the invention can be present as salts or esters, in particular pharmaceutically and veterinarily acceptable salts or esters.
  • salts of the compounds of the invention include suitable acid addition or base salts thereof.
  • suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g.
  • hydrohalic acids such as hydrochloride, hydrobromide and hydroiodide, sulphuric acid, phosphoric acid sulphate, bisulphate, hemisulphate, thiocyanate, persulphate and sulphonic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C 1 -C 4 )-alkyl- or aryl-sul
  • Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2-hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesulphonate, benzenesulphonate, p- chlorobenzenesulphonate and
  • Esters are formed either using organic acids or alcohols/hydroxides, depending on the functional group being esterified.
  • Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acid, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C 1 -C 4 )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-to
  • Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide.
  • Alcohols include alkanealcohols of 1- 12 carbon atoms which may be unsubstituted or substituted, e.g. by a halogen).
  • the invention includes, where appropriate all enantiomers, diastereoisomers and tautomers of the compounds of the invention.
  • the person skilled in the art will recognise compounds that possess optical properties (one or more chiral carbon atoms) or tautomeric characteristics.
  • the corresponding enantiomers and/or tautomers may be isolated/prepared by methods known in the art.
  • Enantiomers are characterised by the absolute configuration of their chiral centres and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Such conventions are well known in the art (e.g. see 'Advanced Organic Chemistry', 3 rd edition, ed. March, J., John Wiley and Sons, New York, 1985).
  • Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone.
  • Some of the compounds of the invention may exist as stereoisomers and/or geometric isomers - e.g. they may possess one or more asymmetric and/or geometric centres and so may exist in two or more stereoisomeric and/or geometric forms.
  • the present invention contemplates the use of all the individual stereoisomers and geometric isomers of those compounds, and mixtures thereof.
  • the terms used in the claims encompass these forms, provided said forms retain the appropriate functional activity (though not necessarily to the same degree).
  • the present invention also includes all suitable isotopic variations of the compound or a pharmaceutically acceptable salt thereof.
  • An isotopic variation of a compound of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 0, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the agent and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e. , 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • the invention includes compounds of general formula (I) where any hydrogen atom has been replaced by a deuterium atom. Isotopic variations of the agent of the present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.
  • Some of the compounds of the invention may exist as atropisomers.
  • Atropisomers are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers.
  • the invention encompasses all such atropisomers.
  • the invention also covers rotamers of the compounds.
  • the invention further includes the compounds of the present invention in prodrug form, i.e. covalently bonded compounds which release the active parent drug in vivo.
  • prodrugs are generally compounds of the invention wherein one or more appropriate groups have been modified such that the modification may be reversed upon administration to a human or mammalian subject. Reversion is usually performed by an enzyme naturally present in such subject, though it is possible for a second agent to be administered together with such a prodrug in order to perform the reversion in vivo. Examples of such modifications include ester (for example, any of those described above), wherein the reversion may be carried out be an esterase etc. Other such systems will be well known to those skilled in the art.
  • the present invention also includes solvate forms of the compounds of the present invention.
  • the terms used in the claims encompass these forms.
  • the solvate is a hydrate.
  • a further aspect of the inventiont relates to a combination comprising a compound as described herein and one or more additional active agents.
  • the one or more compounds of the invention are administered in combination with one or more additional active agents, for example, existing drugs available on the market.
  • the compounds of the invention may be administered consecutively, simultaneously or sequentially with the one or more other active agents.
  • Drugs in general are more effective when used in combination.
  • combination therapy is desirable in order to avoid an overlap of major toxicities, mechanism of action and resistance mechanism(s).
  • the major advantages of combining chemotherapeutic drugs are that it may promote additive or possible synergistic effects through biochemical interactions and also may decrease the emergence of resistance.
  • Beneficial combinations may be suggested by studying the activity of the test compounds with agents known or suspected of being valuable in the treatment of a particular disorder. This procedure can also be used to determine the order of administration of the agents, i.e. before, simultaneously, or after delivery. Such scheduling may be a feature of all the active agents identified herein.
  • compounds of the invention can be used in combination with immunotherapies such as cancer vaccines and/or with other immune-modulators such as agents that block the PD1/PDL-1 interaction.
  • immunotherapies such as cancer vaccines and/or with other immune-modulators such as agents that block the PD1/PDL-1 interaction.
  • agents for use in combination with the presently claimed compounds include immune modulators that block CTLA-4 or LAG-3.
  • the additional active agent is an immunotherapy agent, more preferably a cancer immunotherapy agent.
  • immunotherapy agent refers to a treatment that uses the subject's own immune system to fight diseases such as cancer.
  • the compounds of the invention can be used in combination agents that block or decrease inflammation such as antibodies that target pro-inflammatory cytokines.
  • the compounds of the invention can also be used in combination with other chemotherapy agents and/or in conjunction with radiotherapy.
  • the invention further relates to the compounds of the present invention in their various crystalline forms, polymorphic forms and (an)hydrous forms. It is well established within the pharmaceutical industry that chemical compounds may be isolated in any of such forms by slightly varying the method of purification and or isolation form the solvents used in the synthetic preparation of such compounds.
  • compositions of the present invention may be adapted for rectal, nasal, intrabronchial, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intraarterial and intradermal), intraperitoneal or intrathecal administration.
  • the formulation is an orally administered formulation.
  • the formulations may conveniently be presented in unit dosage form, i.e. , in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose.
  • the formulations may be in the form of tablets and sustained release capsules, and may be prepared by any method well known in the art of pharmacy.
  • Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, gellules, drops, cachets, pills or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution, emulsion or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; or as a bolus etc.
  • these compositions contain from 1 to 250 mg and more preferably from 10-100 mg, of active ingredient per dose.
  • the term "acceptable carrier" includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl-methylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica.
  • Flavouring agents such as peppermint, oil of Wintergreen, cherry flavouring and the like can also be used. It may be desirable
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may be optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
  • compositions suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
  • compositions or emulsions which may be injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally or intramuscularly, and which are prepared from sterile or sterilisable solutions.
  • injectable forms typically contain between 10 - 1000 mg, preferably between 10 - 250 mg, of active ingredient per dose.
  • compositions of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders.
  • the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin.
  • the active ingredient can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required.
  • a person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject without undue experimentation.
  • a physician will determine the actual dosage which will be most suitable for an individual patient and it will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • the dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the dosage amount will further be modified according to the mode of administration of the compound.
  • parenteral administration of a compound is typically preferred.
  • the parenteral dose will be about 0.01 to about 100 mg; preferably between 0.1 and 20 mg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to modulate GPR65.
  • the compounds may be administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg.
  • the precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
  • the compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to achieve one or more of the therapeutic indications disclosed herein.
  • a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 500 mg or about 0.1 to about 50 mg in a manner consistent with the condition of the patient.
  • the oral dose would be about 0.5 to about 50 mg or about 0.5 to about 20 mg.
  • the compounds of this invention which may have good bioavailability, may be tested in one of several biological assays to determine the concentration of a compound which is required to have a given pharmacological effect.
  • AIBN azobisisobutyronitrile
  • AcOH acetic acid
  • BINAP (2,2'-bis(diphenylphosphino)-1 ,T- binaphthyl)
  • Boc tert-butyloxycarbonyl
  • br. broad
  • CAN Ceric ammonium nitrate
  • CBS Corey-Bakshi-Shibata catalyst
  • CCl 4 tektrachloromethane
  • CMBP (Tributylphosphoranylidene)acetonitrile
  • d doublet
  • DAST diethylaminosulfur trifluoride
  • DCM dichloromethane
  • DIAD diisopropyl azodicarboxylate
  • DIBAL diisobutylaluminium hydride
  • DIPEA N, N-diisopropylethylamine
  • DMF N, N- dimethylformamide
  • DMSO dimethylsulfoxide
  • dppf 1 ,
  • Silica gel chromatography was performed on an automated flash chromatography system, such as CombiFlash Companion, CombiFlash Rf system or Reveleris X 2 flash system using RediSep® Rf or Reveleris® or the GraceResolvTM pre-packed silica (230-400 mesh, 40-63 ⁇ m) cartridges.
  • CombiFlash Companion CombiFlash Rf system or Reveleris X 2 flash system using RediSep® Rf or Reveleris® or the GraceResolvTM pre-packed silica (230-400 mesh, 40-63 ⁇ m) cartridges.
  • Analytical LC-MS experiments to determine retention times and associated mass ions were performed using an Agilent 1200 series HPLC system coupled to an Agilent 1956, 6100 or 6120 series single quadrupole mass spectrometer running one of the analytical methods described below or a Shimadzu-2020-P2 system consisting of a Shimadzu LC-20AD series LC system and a Shimadzu-2020, single quadrupole mass spectrometer running one of the analytical methods described below
  • Preparative HPLC purifications were performed either using a Waters Xbridge Prep OBD C18, 10 ⁇ m, 40 x 150 mm column using a gradient of MeCN and 0.1% ammonia in water or a gradient of MeCN and 0.1% formic acid in water. Fractions were collected following UV detection across all wavelengths with PDA and in some cases an SQD2 or ACQUITY QDa mass spectrometer.
  • Preparative SFC purifications were performed using either a Waters SFC prep 15 system, a Waters SFC prep 100 system or a Sepiatec Prep SFC 50 with either a: Phenomenex Lux® Cellulose-4, Column 1 x 25 cm, 5 ⁇ m particle size column or a Chiralpak® IG (Daicel Ltd.) column (1 x 25 cm, 5 ⁇ m particle size) or a Chiralpak IC 10 x 250 mm 5 ⁇ m particle size column or a Chiralpak IA 10 x 250 mm 5 ⁇ m particle size column or a Phenomenex Lux® 5 ⁇ m i-Cellulose-5, LC Column 250 x 21 mm or a a Phenomenex Lux® A1 5 ⁇ m, LC Column 250 x 10 mm or a Chiralpak IH 10 x 250 mm, 5 ⁇ m particle size column or a Chiralpak AY-H 10 x 250 mm, 5 ⁇ m particle size column,
  • NMR spectra were recorded using either a Bruker Avance III HD 500 MHz instrument, a Bruker Avance Neo 400 MHz, Bruker Avance III 400 MHz instrument or a QOne AS400400 MHz spectrometer using either residual non-deuterated solvent, or tetra-methylsilane as a reference
  • enantiomers of the compounds described above can be isolated using techniques well known in the art, including, but not limited to, chiral chromatography.
  • a racemic mixture can be dissolved in a solvent, for example, methanol, followed by separation by chiral SFC on a Waters prep 15 with UV detection by DAD at 210 - 400 nm, 40 °C, 120 bar.
  • the column was Chiralpak IG 10 x 250 mm, 5 ⁇ m, flow rate 15 ml/ min at 45% MeOH (0.1% DEA), 55% CO 2 to afford both enantiomers as the separated pure compounds.
  • Solvents A: 0.05% formic acid in water, B: 0.05% formic acid in MeCN
  • Step 1 tert-Butyl ( ⁇ )-2-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate 1-1 a (2.00 g, 8.88 mmol) and glyoxylic acid monohydrate (1.14 g, 12.4 mmol) were added to a round bottom flask, followed by EtOH (20 ml). Once all solids were in solution an aqueous 2 M sodium hydroxide solution (7.10 ml, 14.2 mmol) was added. The resultant mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo. The aqueous was washed once with DCM (5 ml).
  • Step 2 To a solution of 2-(( ⁇ )-8-(tert-butoxycarbonyl)-2-oxo-8-azabicyclo[3.2.1]octan-3- ylidene)acetic acid 1-1 b (1.6 g, 5.7 mmol) in EtOH (10 ml) was added hydrazine in THF (23 ml, 1 molar, 23 mmol) was added. The resultant mixture was heated to 78 °C for 16 h. The reaction was cooled to RT and concentrated in vacuo. The resultant solid was dissolved in DCM and passed through a hydrophobic frit to remove residual water. Concentrated in vacuo to give a sticky orange solid.
  • Step 3 tert-butyl ( ⁇ )-3-hydroxy-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridazine- 10-carboxylate 1c (471 mg, 1.70 mmol) was dissolved in DCM (4 ml), and a solution of HCI in 1 ,4-dioxane (4.25 ml, 4 molar, 17.0 mmol) was added. The reaction was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo. The resultant brown solid was dissolved in MeOH and agitated over MP-carbonate resin (2.2 g, 6.84 mmol) for 1 h.
  • Step 1 To a solution of 2-(( ⁇ )-8-(tert-butoxycarbonyl)-2-oxo-8-azabicyclo[3.2.1]octan-3- ylidene)acetic acid (4.1 g, 13 mmol) in EtOH (30 ml) at 0 °C was added morpholine (2.3 ml, 27 mmol) was added dropwise. The reaction was stirred at this temperature for 1 h, then allowed to warm to RT and stirred for 72 h.
  • Step 2 To a solution of 2-(( ⁇ )-8-(tert-butoxycarbonyl)-2-oxo-8-azabicyclo[3.2.1]octan-3-yl)- 2-morpholinoacetic acid, morpholine salt 1-1 d (17.02 g, 37.37 mmol) in EtOH (120 ml) was added hydrazine monohydrate in water (11.3 ml, 149.5 mmol). The resultant mixture was heated to 78 °C for 2.5 h. The reaction was cooled to RT and the mixture was concentrated in vacuo. The resultant yellow residue was dissolved in DCM (500 ml) and water (150 ml).
  • the filtrate was concentrated to provide 50:50 mix of tert-butyl ( ⁇ )-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10- carboxylate l-1e and tert-butyl ( ⁇ )-4-morpholino-3-oxo-3,4,4a,5,6,7,8,9-octahydro-2H-6,9- epiminocyclohepta[c]pyridazine-10-carboxylate l-1f as a sticky brown oil.
  • Step 3 To a solution of tert- butyl ( ⁇ )-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9- epiminocyclohepta[c]pyridazine-10-carboxylate 1-1 e and tert-butyl ( ⁇ )-4-morpholino-3-oxo- 3,4,4a,5,6,7,8,9-octahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10-carboxylate l-1f (3.2 g, 66% Mol.
  • Step 4 To a solution of tert-butyl ( ⁇ )-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9- epiminocyclohepta[c]pyridazine-10-carboxylate (2.6 g, 9.4 mmol) in DCM (20 ml) was added a solution of HCI in 1,4-dioxane (23 ml, 4 M, 94 mmol) was added. The reaction was stirred at RT for 72 h. The reaction mixture was concentrated in vacuo to give the HCI salt of 1-1. The HCI salt was dissolved in MeOH (150 ml), AcOH was added and the solution was loaded onto SCX resin (50 g).
  • Step 1 To a mixture of 2-chloro-1-fluoro-4-nitrobenzene l-4a (1 g, 5.70 mmol) and cyclobutanol (1.2 g, 17.09 mmol) in DMF (30 ml) was added CS2CO 3 (6.5 g, 19.94 mmol). The reaction was heated at 80 °C for 16 h, then concentrated in vacuo. The product was purified by silica gel chromatography (5% EtOAc/petroelum ether) to give 2-chloro-1- cyclobutoxy-4-nitrobenzene l-4b as a yellow oil.
  • Step 2 To a solution of 2-chloro-1-cyclobutoxy-4-nitrobenzene l-4b (500 mg, 2.20 mmol) in a mixture of EtOH and saturated aqueous NH4CI solution (12 ml, 1 :1) was added Iron powder (614 mg, 10.98 mmol). The reaction was heated at 80 °C for 2 h, cooled, then concentrated in vacuo. The product was purified by silica gel chromatography (5% EtOAc/petroelum ether) to give 3-chloro-4-cyclobutoxyaniline I-4 as a yellow oil.
  • Step 1 To a suspension of 2-(( ⁇ )-8-(tert-butoxycarbonyl)-2-oxo-8-azabicyclo[3.2.1]octan-3- yl)-2-morpholinoacetic acid, morpholine salt 1-1 d (490 mg, 1.08 mmol) in EtOH (5.0 ml) was added methylhydrazine (229 ⁇ l, 4.30 mmol) and the resulting solution was stirred at 80 °C for 2 h, then at RT for 16 h. The solvent was removed in vacuo. The residue was taken up in DCM (20 ml) and washed with 1 M HCI (20 ml).
  • Step 2 A mixture of tert- butyl ( ⁇ )-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9- epiminocyclohepta[c]pyridazine-10-carboxylate 1-16b and tert-butyl ( ⁇ )-2-methyl-4- morpholino-3-oxo-3,4,4a,5,6,7,8,9-octahydro-2H-6,9-epiminocyclohepta[c]pyridazine-10- carboxylate 1-16a (315 mg, 1.08 mmol) in EtOH (10.0 ml) was added to a vial charged with sodium hydroxide (300 mg, 7.5 mmol) and the mixture was stirred at RT for 1 h.
  • Step 3 To a solution of tert-butyl ( ⁇ )-2-methyl-3-oxo-3,5,6,7,8,9-hexahydro-2H-6,9- epiminocyclohepta[c]pyridazine-10-carboxylate 1-16b (280 mg, 702 ⁇ mol) in DCM (7 ml) was added HCI in dioxane (3.0 ml, 4.0 molar, 12 mmol) and the resulting mixture was stirred at RT for 4 h. The mixture was concentrated in vacuo and the residue was taken up in MeOH and loaded onto SCX ( ⁇ 3 g).
  • 5-Chloro-2-fluoro-4-(6-methoxypyridin-3-yl)aniline l-44 was synthesised from 4-bromo-5- chloro-2-fluoroaniline l-8a and (6-methoxypyridin-3-yl)boronic acid using a procedure essentially the same as for I-32.
  • 6-bromo-2-methyl-3,4-dihydroisoquinolin-1-one (141 mg, 589 ⁇ mol), 5-chloro-2-fluoro-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline l-8b (160 mg, 589 ⁇ mol) and Pd-118 (10.0 mg, 15.3 ⁇ mol) were added to a scintillation vial.
  • the vial was flushed with N2.1.4- Dioxane (3.00 ml) was added, followed by a degassed aqueous solution of potassium phosphate (884 ⁇ l, 2 M, 1.77 mmol). The reaction was heated to 95 °C for 2 h.
  • Methyl 5-(4-amino-2-chloro-5-fluorophenyl)nicotinate l-54 was synthesised from 5-chloro-2- fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline l-8b and methyl 5- bromonicotinate using a procedure essentially the same as for I-47.
  • a 5-Chloro-2-fluoro-4-(5-fluoro-6-methoxypyridin-3-yl)aniline I-66 was synthesised from 4- bromo-5-chloro-2-fluoroaniline l-8a and (5-fluoro-6-methoxypyridin-3-yl)boronic acid using a procedure essentially the same as for I-32.
  • Step 1 To a solution of 5-bromo-2-fluoropyridine (117 ⁇ l, 1.14 mmol) and trifluoroethanol (330 ⁇ l, 4.55 mmol) in THF (2.5 ml) was added a solution of KO‘Bu in THF (2.75 ml, 20% w/w, 4.55 mmol). The reaction was stirred at RT for 24 h before being partitioned between DCM (25 ml) and water (25 ml). The aqueous phase was extracted with additional DCM (25 ml). The organics were combined and washed with water (2 x 50 ml) and brine (50 ml) and dried over magnesium sulphate.
  • Step 2 5-Chloro-2-fluoro-4-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)aniline I-75 was synthesised from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline I- 8b and 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine l-75a using a procedure essentially the same as for I-47.
  • LCMS (Method 2) m/z 321.3, 323.3 (M+H) + (ES + ), at 2.15 min Intermediate 75 (I-75) alternative synthesis
  • Step 1 5-Bromo-2-cyclobutoxypyridine l-76a was synthesised from 5-bromo-2- fluoropyridine and cyclobutanol using a procedure essentially the same as for l-75a.
  • LCMS Method 2 m/z 228.2, 230.3 (M+H) + (ES + ), at 2.14 min
  • Step 1 To a mixture of sodium hydride (145 mg, 60% w/w, 3.64 mmol) in THF (10 ml) and the resulting suspension cooled to 0 °C. To this was added cyclopropanol (0.216 ml, 3.41 mmol) and the resulting suspension stirred at 0 °C for 30 min before 5-bromo-2- fluoropyridine (234 ⁇ l, 2.27 mmol) was added. The resultant mixture was warmed to RT for 6 h. Water (10 ml) was added. The reaction mixture was diluted with a 1:1 mixture of aqueous NaCkNaHCO 3 (25 ml).
  • Step 2 5-Bromo-2-cyclopropoxypyridine l-79a (186 mg, 869 ⁇ mol) and 4, 4, 4', 4', 5, 5,5', 5'- octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (287 mg, 1.13 mmol) were dissolved in a solution of potassium 2-ethylhexanoate in iPrOAc (2.00 ml, 0.5 M, 1.0 mmol). The resulting solution was sparged with N2 before Pd-170 (29.3 mg, 43.4 ⁇ mol) was added. The reaction mixture heated to 50 °C for 50 min.
  • the reaction mixture was allowed to cool to RT for 30 min before 4-bromo-5-chloro-2-fluoroaniline (195 mg, 869 ⁇ mol) and a degassed aqueous solution of K2CO 3 (1.16 ml, 1.5 M,1.74 mmol) were added.
  • the reaction mixture was heated to 50 °C for 3.5 h.
  • the reaction mixture was partitioned between brine (25 ml) and DCM (25 ml).
  • the aqueous was extracted with DCM (25 ml) and the combined organics were concentrated in vacuo.
  • 5-Chloro-2-fluoro-4-(2-fluoropyridin-4-yl)aniline 1-91 was synthesised from 4-bromo-5- chloro-2-fluoroaniline l-8a and 5-chloro-2-fluoro-4-(2-fluoropyridin-4-yl)aniline using a procedure essentially the same as for I-32.
  • Step 1 2-Fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline
  • I- 92b was synthesised from 4-bromo-2-fluoro-5-(trifluoromethyl)aniline l-92a using a procedure essentially the same as for l-8b.
  • Step 2 4-([1 ,2,5]Oxadiazolo[3,4-b]pyridin-6-yl)-2-fluoro-5-(trifluoromethyl)aniline I-92 was synthesised from 2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)aniline l-92b and 6-bromo-[1 ,2,5]oxadiazolo[3,4-b]pyridine using a procedure essentially the same as for I-47.
  • reaction mixture was filtered through celite, the filtrate was diluted in EtOAc.
  • the reaction mixture was diluted with water (25 ml) and the layers were separated. The organics were washed with brine (25 ml), dried over MgSO 4 and concentrated in vacuo.
  • the product was purified by chromatography on silica gel (10-100% EtOAc/DCM) to afford 5-chloro-2-fluoro-4-(pyrazin- 2-yl)aniline I-94 as a white solid.
  • Step 1 To a solution of 5-bromo-2-fluoropyridine (200 mg, 1.14 mmol) and oxetan-3-ol (299 ⁇ l, 4.55 mmol) in THF (2.50 ml) was added a solution of KO‘Bu in THF (2.75 mL, 20% w/w, 4.55 mmol). The reaction was stirred at RT for 24 h. The reaction mixture was diluted with DCM (25 ml) and water (25 ml) and the layers were separated. The aqueous phase was extracted with DCM (25 ml). The combined organics were washed with water (2 x 50 ml) and brine (50 ml) and dried over MgSO 4 .
  • Step 2 5-chloro-2-fluoro-4-(6-(oxetan-3-yloxy)pyridine-3-yl)aniline l-94 was synthesised from 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine l-94a and 5-chloro-2-fluoro-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline l-8b using a procedure essentially the same as for I-47.
  • LCMS Method 2
  • Step 1 To a solution of 1-chloro-2,4-difluoro-5-nitrobenzene 1-101 a (580 mg, 3.00 mmol) and benzo[c][1,2,5]oxadiazol-5-ol 1-101b (410 mg, 3.02 mmol) in MeCN (20 ml) was added K2CO 3 (1.24 g, 8.98 mmol). The reaction was stirred at RT for 3 h. The reaction mixture was diluted with water (5 ml) before the product was extracted with DCM (3 x 10 ml). The combined organics were concentrated in vacuo.
  • Step 2 To a solution of 5-(4-chloro-5-fluoro-2-nitrophenoxy)benzo[c][1 ,2,5]oxadiazole I- 101c (70mg, 0.23 mmol) in EtOH (2 ml) was added a saturated aqueous NH4CI solution (1 ml) and Fe (50 mg, 0.90 mmol). The reaction was stirred at 80 °C for 30 mins. The reaction mixture was cooled and filtered and diluted with water (5 ml). The product was extracted with DCM (3 x 10 ml). The combined organics were concentrated in vacuo.
  • Step 1 To a solution of 1-chloro-4-fluoro-2-methyl-5-nitrobenzene l-102a (3 g, 15.8 mmol) in CCI 4 (60 ml) was added AIBN (260 mg, 1.58 mmol) and NBS (3.1 g, 17.38 mmol) at RT. The mixture was heated at 80 °C for 16 h. The reaction mixture was concentrated in vacuo. The product was purified by chromatography on silica gel (1 % EtOAc/petroelum ether) to give 1-(bromomethyl)-2-chloro-5-fluoro-4-nitrobenzene 1-102b as a colourless oil.
  • Step 2 To a solution of 1-(bromomethyl)-2-chloro-5-fluoro-4-nitrobenzene 1-102b (2 g, 5.61 mmol) in MeCN (45 ml) was added K2CO 3 (2.33 g, 16.83 mmol) and phenol (528 mg, 5.61 mmol). After stirring at RT for 2 h, the mixture was diluted with water (10 ml). The product was extracted with DCM (3 x 30 ml). The combined organics were dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 3 To a solution of 1-chloro-4-fluoro-5-nitro-2-(phenoxymethyl)benzene l-102c (200 mg, 0.71 mmol) in EtOH (4 ml) was added a solution of NH4CI (305 mg, 5.68 mmol) in water (2 ml) and Fe (200 mg, 3.55 mmol) at RT. After stirring at 70 °C for 2 h, the reaction mixture was quenched with water (10 ml) and the product was extracted with DCM (3 x 30 ml). The combined organics were dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 1 To a solution of 2-chloro-5-fluorophenol l-103a (200 mg, 1.37 mmol) in EtOH (5 ml) was added Fe(NOs)3-9H2O (553 mg,1.37 mmol). The solution was stirred at 85 °C for 4 h. The mixture was filtered and the filtrate was concentrated in vacuo. The product was purified by prep-TLC (50% EtOAc/petroleum ether) to give 2-chloro-5-fluoro-4-nitrophenol I- 103b as a yellow solid.
  • Step 2 To a solution of 2-chloro-5-fluoro-4-nitrophenol 1-103b (163 mg, 0.85 mmol) in MeCN (4 ml) was added benzyl bromide (145 mg, 0.85 mmol) and K2CO 3 (352 mg, 2.55 mmol). The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was cooled and diluted with water (20 ml) and the product was extracted with DCM (3 x 20 ml). The combined organics were dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 3 4-(Benzyloxy)-5-chloro-2-fluoroaniline 1-103 was synthesised from 1-(benzyloxy)-2- chloro-5-fluoro-4-nitrobenzene 1-103c using a procedure essentially the same as for 1-101.
  • LCMS Method 5
  • Step 1 To a solution of 1-(bromomethyl)-2-chloro-5-fluoro-4-nitrobenzene l-102b (236 mg, 0.88 mmol) in MeCN (3 ml) were added K 2 CO 3 (367 mg, 2.65 mmol) and 6-fluoropyridin-3- ol (100 mg, 0.88 mmol). After stirring at RT for 2 h, the reaction was diluted with water (10 ml). The product was extracted with DCM (3 x 30 ml), the combined organics were dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 2 To a solution of 5-((2-chloro-5-fluoro-4-nitrobenzyl)oxy)-2-fluoropyridine l-110-a (100 mg, 0.33 mmol) in EtOH (4 ml) was added Fe (94 mg, 1.66 mmol) and a solution of NH4CI(144 mg, 2.66 mmol) in water (2 ml) at RT. After stirring at 70 °C for 2 h, the reaction was diluted with water (10 ml). The product was extracted with DCM (3 x 30 ml). The combined organics were dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 1 To a solution of 1-chloro-2,4-difluoro-5-nitrobenzene 1-101b (159 mg, 0.82 mmol) and benzo[c][1 ,2,5]oxadiazol-5-ol 1-101 a (112 mg, 0.82 mmol) in MeCN (10 ml) was added K2CO 3 (341 mg, 2.47 mmol). The reaction was stirred at RT for 3 h. The reaction mixture was diluted with water (5 ml) and the product was extracted with DCM (3 x 10 ml).
  • Step 2 To a solution of 5-(2-chloro-5-fluoro-4-nitrophenoxy)benzo[c][1 ,2,5]oxadiazole I- 111a (130 mg 0.42 mmol) in EtOH (4 ml) was added a saturated aqueous solution of NH4CI (2 ml) and Fe (94 mg, 1.68 mmol). The reaction was stirred at 80 °C for 30 min. The reaction mixture was filtered and diluted with water (5 ml) before the product was extracted with DCM (3 x 10 ml).
  • Step 1 To a solution of methyl 4-bromo-2-chloro-5-fluorobenzoate 1-113a (400 mg, 1.49 mmol) in THF (3 ml) was added a solution of DIBAL in hexanes (3.8 ml, 1 M, 3.80 mmol) at RT. The resultant reaction mixture was stirred at RT for 2 h. Water (15 ml) was added and the product was extracted with EtOAc (3 x 15 ml). The combined organics were washed with brine (15 ml), dried over Na 2 SO 4 and concentrated in vacuo to give (4-bromo-2-chloro- 5-fluorophenyl)methanol 1-113b as a white solid.
  • Step 2 To a solution of benzo[c][1 ,2,5]oxadiazol-5-ol (227 mg, 1.67 mmol), (4-bromo-2- chloro-5-fluorophenyl)methanol 1-113b (400 mg, 1.67 mmol) and triphenylphosphine (879 mg, 3.34 mmol) in THF (20 ml) at 0 °C was added DIAD (674 mg, 3.34 mmol). The reaction was stirred at RT for 16 h. Water (40 ml) was added and the product was extracted with EtOAc (3 x 40 ml). The combined organics were washed with brine (40 ml), dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 3 To a solution of 5-((4-bromo-2-chloro-5-fluorobenzyl)oxy)benzo[c][1,2,5]oxadiazole 113c (300 mg, 0.84 mmol), diphenylmethanimine (152 mg, 0.84 mmol), Pd(OAc)2 (19 mg, 0.084 mmol) and BINAP (53 mg, 0.084 mmol) in 1 ,4-dioxane (10 ml) was added Cs 2 CO 3 (819 mg, 2.52 mmol). The reaction was stirred at 100 °C for 16 h. The reaction was cooled to RT.
  • Step 1 To a solution of 6-Chloro-3-nitropyridin-2-ylamine 1-121 a (1.00 g, 5.76 mmol) in acetone (60 ml) was added PIDA (4.64 g, 14.4 mmol). The reaction mixture was heated to 80 °C for 6 h. The reaction was concentrated in vacuo. The product was purified by chromatography on silica gel (0-100% EtOAc/DCM) to afford 5-chloro-[1,2,5]oxadiazolo[3,4- b]pyridine 1-oxide l-121b as a yellow solid.
  • Step 2 A solution of 5-chloro-[1 ,2,5]oxadiazolo[3,4-b]pyridine 1-oxide 1-121 b (403 mg, 2.35 mmol) in DCM (60 ml) was cooled at 0 °C and triphenylphosphine (924 mg, 3.52 mmol) was added. The reaction mixture was warmed to RT and stirred for 16 h. A 1M aqueous NaOH solution (30 ml) was added and the mixture was vigorously stirred for 15 min. The product was extracted with DCM (3 x 50 ml). The combined organics were dried over sodium sulphate and concentrated in vacuo.
  • Step 3 4-([1,2,5]Oxadiazolo[3,4-b]pyridin-5-yl)-5-chloro-2-fluoroaniline 1-121 was synthesised from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline I- 8b and 5-chloro-[1,2,5]oxadiazolo[3,4-b]pyridine 1-121c using a procedure essentially the same as for l-47.
  • 5-Chloro-4-(6-(difluoromethoxy)pyridin-3-yl)-2-fluoroaniline 1-122 was synthesised from 5- chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline l-8b and 5-bromo-2- (difluoromethoxy)pyridine 1-122a using a procedure essentially the same as for I-47.
  • Step 1 To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene l-123a (3.7 g, 16.55 mmol) in CCk (30 ml) were added NBS (3.2 g, 18.21 mmol) and AIBN (272 mg, 0.27 mmol,) at RT. The reaction was then stirred at 80 °C for 16 h. Water (15 ml) was added and the mixture was extracted with EtOAc (3 x 15 ml).
  • Step 2 To a solution of 1-bromo-4-(bromomethyl)-5-chloro-2-fluorobenzene l-123b (1.0 g, 3.30 mmol) in MeCN (10 ml) were added 5-fluoropyridin-3-ol (374 mg, 3.30 mmol) and K2CO 3 (1.3 g, 9.92 mmol). The reaction was stirred at RT for 1 h. Water (10 ml) was added and the mixture was extracted with EtOAc (3 x 20 ml). The combined organics were washed with brine (15 ml), dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 3 To a solution of 3-((4-bromo-2-chloro-5-fluorobenzyl)oxy)-5-fluoropyridine 1-123c (377 mg, 1.12 mmol) in 1 ,4-dioxane (3 ml) were added diphenylmethanimine (204 mg, 1.12 mmol), Pd2(dba)3 (116 mg, 0.11 mmol), CS 2 CO 3 (917 mg, 2.81 mmol) and Xantphos (130 mg, 0.22 mmol). The reaction was stirred at 110 °C for 3 h. Water (20 ml) was added and the mixture was extracted with EtOAc (3 x 20 ml).
  • Step 4 To a solution of N- (5-chloro-2-fluoro-4-(((5-fluoropyridin-3-yl)oxy)methyl)phenyl)- 1,1-diphenylmethanimine 1-123d (72 mg, 0.16 mmol) in 1 ,4-dioxane (6 ml) and water (1.4 ml) was added TFA (14 drops). The reaction was stirred at RT for 10 min. The pH of the reaction mixture was adjusted to 8 by the addition of saturated aqueoues NaHCO 3 and the product was extracted with EtOAc (3 x 5 ml).
  • 5-Chloro-2-fluoro-4-(6-isobutoxypyridin-3-yl)aniline 1-125 was synthesised from 5-chloro-2- fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and 2-methylpropan-1-ol using a procedure essentially the same as for 1-106.
  • Step 1 6-Bromo-4-fluorobenzo[c][1 ,2,5]oxadiazole 1-oxide 1-127b was synthesised from 4- bromo-2-fluoro-6-nitroaniline 1-127a and PI DA using a procedure essentially the same as for 1-121 b.
  • 1 H N MR 400 MHz, DMSO-d6) ⁇ 7.96 (s, 1 H), 7.83 - 7.57 (m, 1H).
  • Step 2 To a solution of 5-bromo-7-fluorobenzo[c][1 ,2,5]oxadiazole 1-oxide 1-127b (499 mg, 2.08 mmol) in EtOH (1.50 ml) was added triethyl phosphite (535 ⁇ l, 3.12 mmol) and the reaction mixture was heated to 70 °C for 2 h. The reaction was cooled to RT, diluted with DCM (15 ml) and 10% v/v aqueous sodium hypochlorite, then vigorously stirred for 20 min after which the dark brown solution passed through a phase separator and the filtrate was concentrated in vacuo.
  • Step 3 6-Bromo-4-fluorobenzo[c][1 ,2,5]oxadiazole 1-127 was synthesised from 5-chloro-2- fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline l-8b and 6-bromo-4- fluorobenzo[c][1 ,2,5]oxadiazole 1-127c using a procedure essentially the same as for I-47.
  • Step 1 5-Bromo-2-fluoro-4-(6-fluorobenzo[c][1,2,5]oxadiazol-5-yl)aniline l-128b was synthesised from 4-bromo-2-fluoro-6-nitroaniline 1-128a and PI DA using a procedure essentially the same asforl-121b.
  • Step 2 5-Bromo-2-fluoro-4-(6-fluorobenzo[c][1,2,5]oxadiazol-5-yl)aniline l-128c was synthesised from triethyl phosphite and 5-bromo-2-fluoro-4-(6- fluorobenzo[c][1,2,5]oxadiazol-5-yl)aniline l-128b using a procedure essentially the same asforl-121b.
  • Step 3 5-Chloro-2-fluoro-4-(6-fluorobenzo[c][1,2,5]oxadiazol-5-yl)aniline I-28 was synthesised from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline I- 8b and 6-bromo-4-fluorobenzo[c][1,2,5]oxadiazole 1-128b using a procedure essentially the same as for I-47.
  • Step 1 5-Bromo-4-fluorobenzo[c][1 ,2,5]oxadiazole 1-oxide l-129b was synthesised from 4- bromo-3-fluoro-2-nitroaniline 1-129a and PIDA using a procedure essentially the same as for l-121 b.
  • Step 2 5-Bromo-4-fluorobenzo[c][1 ,2,5]oxadiazole 1-129c was synthesised from 5-Bromo- 4-fluorobenzo[c][1 ,2,5]oxadiazole 1-oxide 1-129b and triethyl phosphite using a procedure essentially the same as for 1-121 b.
  • Step 3 5-chloro-2-fluoro-4-(4-fluorobenzo[c][1 ,2,5]oxadiazol-5-yl)aniline 1-129 was synthesised from 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline I- 8b and 5-Bromo-4-fluorobenzo[c][1 ,2,5]oxadiazole 1-129c using a procedure essentially the same as for l-47.
  • 5-Chloro-2-fluoro-4-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)aniline 1-130 was synthesised from 5-chloro-4-(5,6-difluoropyridin-3-yl)-2-fluoroaniline I-90 and trifluoroethanol using a procedure essentially the same as for 1-106.
  • Step 1 To a solution of 4-(5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-5-chloro-2- fluoroaniline 128-3 (300 mg, 818 ⁇ mol) in DCM (4 ml) was added Et3N (251 ⁇ l, 1.80 mmol) followed by di-tert-butyl dicarbonate (282 ⁇ l, 1.23 mmol). The reaction mixture was stirred at RT for 16 h. A further portion of EtsN (114 ⁇ l, 818 ⁇ mol) and di-tert-butyl dicarbonate (94 ⁇ l, 409 ⁇ mol) were added and the reaction was further stirred at RT for 24 h.
  • Step 2 A solution of tert- butyl (4-(5-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-5- chloro-2-fluorophenyl)carbamate 1-132a (201 mg, 430 ⁇ mol) in THF (5 ml) was cooled to 0 °C and a solution of TBAF in THF (646 ⁇ l, 1 M, 646 ⁇ mol) was added and the reaction mixture was slowly warmed to RT and stirred for 18 h. The reaction mixture was diluted with an aqueous saurated solution of NaHCO 3 (25 ml) and the product was extracted with DCM (3 x 10 ml).
  • Step 3 To a solution of tert- butyl (5-chloro-2-fluoro-4-(5-(hydroxymethyl)pyridin-3- yl)phenyl)carbamate 1-132b (141 mg, 332 ⁇ mol) in DCM (5 ml) and THF (2 ml) was added manganese dioxide (173 mg 1 .99 mmol). The reaction mixture was stirred at RT for 24 h. The reaction was filtered on celite, the celite pad was rinsed with DCM and THF (50 ml).
  • Step 4 To a suspension of tert-butyl (5-chloro-2-fluoro-4-(5-formylpyridin-3- yl)phenyl)carbamate 1-132c (114 mg, 325 ⁇ mol) in DCM (10.0 ml) at -20 °C was slowly added DAST (172 ⁇ l, 1.30 mmol). The reaction was slowly warmed to RT and stirred at RT for 4 h. A saturated aqueous solution of NaHCO 3 (20 ml) was added and the product was extracted with DCM (3 x 15 ml). The combined organics were washed with brine (20 ml), dried with MgSO4 and concentrated in vacuo.
  • Step 5 To a solution of tert- butyl (5-chloro-4-(5-(difluoromethyl)pyridin-3-yl)-2- fluorophenyl)carbamate (88.0 mg, 236 ⁇ mol) in DCM (3 ml) at 0 °C was added HCI in 1,4- dioxane (590 ⁇ l, 4 M, 2.36 mmol) and the reaction mixture was left to warm to RT and stirred at RT for 1 h. A further portion of HCI in 1 ,4-dioxane (3 mL, 4 M 12.0 mmol) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo to give a white solid.
  • 5-Chloro-4-(6-((2,2-difluorocyclopropyl)methoxy)pyridin-3-yl)-2-fluoroaniline 1-135 was synthesised from 5-chloro-2-fluoro-4-(6-fluoropyridin-3-yl)aniline I-33 and (2,2- difluorocyclopropyl)methanol using a procedure essentially the same as for 1-133.
  • the reaction mixture was stirred at RT for 3 h.
  • the reaction mixture was treated with MTBE (20 ml) and left to settle for 72 h.
  • the resultant suspension was filtered and the solid was washed with MTBE.
  • the solids were dissolved in MeOH (100 ml) and treated with MP-carbonate resin (1 g, 3 mmol) and the suspension was stirred at RT for 18 h.
  • Step 1 tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate l-3a (10 g, 44 mmol) was dissolved in 1 ,1-dimethoxy-A/,N- dimethylmethanamine (24 ml, 0.18 mol) and the reaction mixture was heated at reflux for 16 h. The solvent was removed in vacuo.
  • Step 2 To a solution of urea (0.2 g, 4 mmol) in EtOH (10 ml) was added a solution of sodium ethoxide (2 ml, 21 % w/w in EtOH, 4 mmol).
  • a solution of sodium ethoxide (2 ml, 21 % w/w in EtOH, 4 mmol).
  • tert-Butyl (E)-2- ((dimethylamino)methylene)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate l-3b (1 g, 4 mmol) in EtOH (10 ml) was added and the reaction mixture was heated to 90 °C for 16 h.
  • Step 3 To a solution of tert- butyl ( ⁇ )-2-oxo-3,5,6,7,8,9-hexahydro-2H-5,8- epiminocyclohepta[d]pyrimidine-10-carboxylate l-3c (600 mg, 1.73 mmol) in DCM (17 ml) was added HCI in 1 ,4-dioxane (4.33 ml, 4.0 molar, 17.3 mmol) and the mixture was stirred at RT for 16 h. The precipitate was filtered and washed with DCM (2 x 10 ml).
  • Step 2 To a solution of (E)-N-((2-chloro-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2- sulfinamide (I5b) (13.6 g, 51.8 mmol) in THF (79 ml) was added a solution of 3- butenylmagnesium bromide (0.5 M, 11.4 ml) at 0 °C. The mixture was warmed to RT for 1 h. Water (50 ml) was added at 0 °C, and the product was extracted with EtOAc (3 x 30 ml). The combined organics were washed with brine and dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 3 To a solution of N- (1-(2-chloro-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane- 2-sulfinamide (I5c) (15.0 g, 47.1 mmol) in MeOH (104 ml) was added a solution of HCI in EtOAc (4 M, 33.0 ml) at 0 °C. The mixture was warmed to RT for 1 hr. The mixture was concentrated in vacuo, the residue was triturated with MTBE (20 ml) at RT for 30 min. The mixture was filtered. The filter cake was combined and washed with MTBE (2 x 10 ml) and concentrated in vacuo to give a yellow solid.
  • Step 4 To a solution 1-(2-chloro-6-fluoropyridin-3-yl)pent-4-en-1 -amine (I5d) (5.52 g, 23.4 mmol) and 4-methoxyphenylboronic acid (7.11 g, 46.8 mmol) in 1 ,4-dioxane (300 ml) was added Cu(OAc) 2 (10.6 g, 58.5 mmol), 4 ⁇ molecular sieves (10.0 g) and Et 3 N (4.23 ml, 30.4 mmol) at RT. The mixture was warmed to 35 °C for 16 h. The reaction mixture was filtered.
  • Step 5 To a solution of N- (1-(2-chloro-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline (l-5e) (3.00 g, 9.35 mmol) in toluene (60 ml) was added NaO‘Bu (1.35 g, 14.0 mmol) and Pd-172 (567 mg, 935 umol) at 20 °C. The mixture was stirred at 110 °C for 16 h. The reaction mixture was concentrated in vacuo.
  • Step 6 To a solution of ( ⁇ )-2-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[b]pyridine (l-5f) (113 mg, 397 ⁇ mol) in MeOH (4 ml) was added a solution of sodium methoxide in methanol (110 ⁇ l, 5.4 molar, 596 ⁇ mol). The resultant mixture was heated at 65 °C for 20 h. THF (1 ml) was added followed by a further portion of sodium methoxide (110 ⁇ l, 5.4 molar, 596 ⁇ mol). The reaction was stirred at 65 °C for a further 24 h.
  • Step 7 To a solution of ( ⁇ )-2-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[b]pyridine (l-5g) (424 mg, 1.43 mmol) in MeCN (21 ml) at 0 °C was added a solution of CAN (2.51 g, 4.58 mmol) in water (21 ml) dropwise. After the addition the reaction was stirred at 0 °C for 1 h. 2 M NaOH (25 ml) was added and the mixture was filtered. DCM was added and the precipitate was washed with DCM and water.
  • Step 1 To a solution of 3-chloro-2-fluoroisonicotinaldehyde l-6a (1.00 g, 6.27 mmol) in THF (17 ml) was added titanium (IV) ethoxide (2.63 ml, 12.5 mmol) in one portion at RT. The mixture was stirred at RT for 5 min before (S)-tert-butylsulfinamide (760 mg, 6.27 mmol) was added in one portion. The resulting mixture was stirred at RT for 16 h. Brine (30 ml) was added, and the mixture stirred for 10 min then filtered through celite. The filtrate was extracted with EtOAc (2 x 20 ml).
  • Step 2 To a solution of (S)-N-((3-chloro-2-fluoropyridin-4-yl)methylene)-2-methylpropane-2- sulfinamide (1.38 g, 5.26 mmol) (l-6b) in THF (22 ml) was added but-3-en-1-yl magnesium bromide (31.6 ml, 0.5 M, 15.8 mmol) dropwise at -78 °C. The mixture was warmed to RT slowly and stirred for 72 h. Saturated NH4CI solution (10 ml) was added and the product was extracted with EtOAc (3 x 10 ml). The combined organics were dried with MgSO4 and concentrated in vacuo.
  • Step 3 To a solution of (S)-/(R)-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1-yl)-2- methylpropane-2-sulfinamide (l-6c) (714 mg, 2.015 mmol) in ‘BuOH (7.2 ml) was added a solution of HCI in 1 ,4-dioxane (3.0 ml, 4 M, 12.09 mmol) at RT and stirred for 2.5 h. The reaction mixture was quenched with saturated aqueous NaHCO 3 solution (100 ml) and extracted with DCM (3 x 30 ml).
  • Step 4 To a sollon of (R)-1-(3-chloro-2-fluoropyridin-4-yl)pent-4-en-1 -amine (l-6d) (644.3 mg, 3.001 mmol), (4-methoxyphenyl)boronic acid (1.37 g, 9.0 mmol), and Cu(OAc)2 (820 mg, 4.50 mmol) in DCM (100 ml) was added pyridine (1.2 ml, 15.0 mmol) dropwise. The mixture was stirred at RT, open to air for 16 h. 2M NaOH aqueous solution (20 ml) was added followed by water (20 ml) and the mixture extracted with DCM (3 x 20 ml).
  • Step 5 A three-neck flask was charged with Pd-178 (7.4 mg, 15.6 ⁇ mol) and sodium tert- butoxide (22.5 mg, 234 ⁇ mol) and purged with N2.lsolution of (R)-N-(1-(3-chloro-2- fluoropyridin-4-yl)pent-4-en-1-yl)-4-methoxyaniline (l-6e) (50.0 mg, 156 ⁇ mol) in toluene (1 ml) was added dropwise. The resulting mixture was heated to 95 °C for 1 .5 h. The reaction mixture was cooled to RT and filtered through celite, washing with EtOAc (3 x 20 ml). The filtrate was concentrated in vacuo.
  • Step 6 A solution of (5R,8S)-1-fluoro-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-5,8- epiminocyclohepta[c]pyridine (l-6f) (69 mg, 232 ⁇ mol) in MeCN (3.2 ml) was cooled to 0 °C before a solution of CAN (381 mg, 696 ⁇ mol) in water (3.2 ml) was added dropwise. After the addition was complete, the reaction was stirred for 1 h at 0 °C.2 M aqueous NaOH (5 ml) and water (5 ml) were added, and the mixture extracted with DCM (3x10 ml).
  • Step 1 (S)-N-((4-Bromo-6-fluoropyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide
  • I- 7b was synthesised from 4-bromo-6-fluoronicotinaldehyde l-7a using a procedure essentially the same as for l-6b.
  • Step 2 To a solution of ((S)-N-((4-bromo-6-fluoropyridin-3-yl)methylene)-2-methylpropane- 2-sulfinamide l-7b (7.00 g, 22.8 mmol) in THF (114 ml) was added but-3-en-1-yl magnesium bromide (2.54 M, 17.9 ml, 45.6 mmol) dropwise at -78 °C. The mixture was warmed to RT slowly and stirred for 16 h. Saturated NH 4 CI solution (10 ml) was added and the product was extracted with EtOAc (2 x 10 ml). The combined organics were dried with MgSO 4 and concentrated in vacuo.
  • Step 3 ( ⁇ )-1-(4-Bromo-6-fluoropyridin-3-yl)pent-4-en-1-amine l-7d was synthesised from ( ⁇ )-N-(1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide l-7c using a procedure essentially the same as for l-6d.
  • LCMS (Method 1) m/z 259.2, 261.2 (M+H) + (ES + ), at 1.21 min.
  • Step 4 ( ⁇ )-N-(1-(4-Bromo-6-fluoropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline l-7e was synthesised from ( ⁇ )-1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en-1-amine l-7d using a procedure essentially the same as for l-6e.
  • LCMS Method 1 m/z 365.0, 367.1 (M+H) + (ES + ), at 1.76 min.
  • Step 5 A three-neck flask was charged with Pd-178 (0.29 g, 0.61 mmol) and NaO‘Bu (0.88 g, 9.2 mmol) and purged with N2.
  • a solution of N- (1-(4-bromo-6-fluoropyridin-3-yl)pent-4-en- 1-yl)-4-methoxyaniline l-7e (2.3 g, 6.1 mmol) in toluene (66 ml) was added dropwise.
  • the resulting mixture was heated to 95 °C for 2 h.
  • the reaction mixture was cooled to RT and filtered through celite, washing the solid with EtOAc (150 ml). The filtrate was concentrated in vacuo.
  • the product was purified by silica gel chromatography (0%-50% EtOAc/isohexane) to give a mixture of enantiomers which were dissolved to 30 mg/ml in DCM: methanol (1 :4) and was then separated by chiral SFC on a Waters prep 15 with UV detection at 210 nm, 40 °C, 100 baron a Lux C3 column (21.2 mm x250 mm, 5 ⁇ m particle size), flow rate 50 ml/min using 40% methanol to give (6S,9R)-3-fluoro-10-(4- methoxyphenyl)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine (l-7f) as a pale yellow solid.
  • Step 7 (6S,9R)-3-Fluoro-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[c]pyridine I-6 (300 mg, 1.68 mmol) was dissolved in HBr (1.90 ml, 48 % w/w in water, 16.8 mmol) and was heated at 100 °C for 18 h.
  • Step 1 To a solution of 4,6-dichloronicotinaldehyde l-7i (17.3 g, 88.5 mmol) and (S)-2- methylpropane-2-sulfinamide (10.7 g, 88.5 mmol) in DCM (150 ml) was added cesium carbonate (28.8 g, 88.5 mmol). The resultant mixture was stirred at RT for 16 h. The material was filtered and the solid residue was washed with DCM (150 ml). The solvent was evaporated to give (S)-N-((4,6-dichloropyridin-3-yl)methylene)-2-methylpropane-2- sulfinamide l-7j as an off white solid.
  • 1 H NMR 400 MHz, DMSO-d6) ⁇ 8.97 (s, 1 H), 8.76 (s, 1H), 8.04 (s, 1 H), 1.21 (s, 9H).
  • Step 2 A solution of but-3-en-1-ylmagnesium bromide (0.5 M in THF) (60.9 ml, 30.4 mmol) was slowly added to a solution of (S)-N-((4,6-dichloropyridin-3-yl)methylene)-2- methylpropane-2-sulfinamide l-7j (5.00 g, 1 Eq, 17.9 mmol) in THF (100 mL) at -78 °C. The reaction mixture was allowed to slowly warm up to RT over 16 h. The reaction was cooled to 0-10 °C and saturated aqueous NH4CI (100 ml) was added and stirred for 5 min.
  • Step 3 A solution of HCI (4 M in dioxane) (41 ml, 0.16 mol) was added to a solution of (S)- N- ((R)-1-(4,6-dichloropyridin-3-yl)pent-4-en-1-yl)-2-methylpropane-2-sulfinamide l-7k (11 g, 33 mmol) in ‘BuOH (50 ml) and the reaction mixture was stirred at RT for 90 min. The reaction mixture was cooled in an ice bath and water (220 ml) was added and stirred for 10 min. The aqueous was extracted with MTBE (3 x 30 ml). The organic layer was extracted with water (2 x 30 ml).
  • Step 4 To a solution of (R)-1-(4,6-dichloropyridin-3-yl)pent-4-en-1-amine I-7I (7.04 g, 30.5 mmol) in DCM (70 ml) was added (4-methoxyphenyl)boronic acid (13.9 g, 91.4 mmol), copper (II) acetate (6.09 g, 33.5 mmol) and EtsN (21.2 ml, 152 mmol). The resultant mixture was stirred at RT for 20 h.
  • Step 5 To a solution of (R)-N-(1-(4,6-dichloropyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline l-7m (2.73 g, 8.10 mmol) in toluene (20 ml) was added N, N- dimethylethane-1 ,2-diamine (86.8 ⁇ l, 810 ⁇ mol), copper(l) iodide (30.8 mg, 162 ⁇ mol) and sodium methoxide (656 mg, 243 ⁇ mol). The resultant mixture was heated at 100 °C for 96 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo.
  • Step 6 Pd-161 (763.6 mg, 1.65 mmol) and NaO t Bu (2.38 g, 24.8 mmol) were placed in a 3- necked RB flask, which was purged under vacuum and backfilled with N2 (3 times).
  • (R)-N- (1-(4-chloro-6-methoxypyridin-3-yl)pent-4-en-1-yl)-4-methoxyaniline l-7n (5.79 g, 16.52 mmol) was purged under vacuum and backfilled with N2 (3 times).
  • Toluene (180 ml) was added to amine and the resultant solution was transferred to the 3-necked RB flask.
  • Step 7 To a solution of (6S,9R)-3-methoxy-10-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H- 6,9-epiminocyclohepta[c]pyridine l-7o (2.00 g, 6.61 mmol) in MeCN (75 ml) and water (75 ml) was added sulfuric acid (6.6 ml, 1 M, 6.61 mmol) followed by trichloroisocyanuric acid (769 mg, 3.31 mmol). The reaction mixture was stirred at RT for 16 h. The mixture was extracted with DCM (3 x 200 ml). The combined organics were extracted with water (50 ml).
  • the aqueous layer was basified with KOH (3.6 ml, 5 M) and extracted with 10% MeOH in DCM (300 ml). More KOH (1.8 ml, 5 M) was added and the aqueous layer was extracted with 10% MeOH in DCM (100 ml). A further portion of KOH (1.8 ml, 5 M) was added and the aqueous layer was extracted with 10% MeOH in DCM (150 ml). The combined organics were dried over Na 2 SO 4 and concentrated in vacuo to give
  • Step 8 A solution of (6S,9R)-3-methoxy-6,7,8,9-tetrahydro-5H-6,9- epiminocyclohepta[c]pyridine l-7p (0.99 g, 5.2 mmol) in HBr (48% in water) (8.8 ml, 78 mmol) was heated at reflux for 16 h. The mixture was concentrated in vacuo and the concentrate was diluted with MeOH, loaded onto a SCX cartridge (80 g), the cartridge was washed with MeOH and the product was eluted with NH3 in MeOH solution (0.7M).
  • Step 1 To a mixture of 4-bromo-5-chloro-2-fluoroaniline l-8a (300 mg, 1.34 mmol) in 1 ,4- dioxane (5 ml) was added bis(pinacolato)diboron (509 mg, 2.00 mmol), KOAc (394 mg, 4.00 mmol) and Pd(dppf)Cl2 (98 mg, 0.13 mmol) under N2. The reaction mixture was heated at reflux for 1 h then poured into water and the product was extracted with DCM (2 x 20 ml). The combined organics were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 2 To a mixture of 5-chloro-2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) aniline l-8b (314 mg, 1.16 mmol) in a mixture of 1 ,4-dioxane (5 ml) and water (1 ml) were added 2-bromo-5-methyl-1,3,4-thiadiazole (138 mg, 0.77 mmol), Na2CO 3 (245 mg, 2.31 mmol) and Pd(PPh 3 ) 4 (89 mg, 0.08 mmol) under N2. The reaction was heated at 100 °C for 16 h, then poured into water and extracted with DCM (2 x 20 ml).
  • Step 1 A mixture of tert-butyl (4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)carbamate 1-10a (413.0 mg, 1.29 mmol), 2-bromo-5-(trifluoromethyl)-1 ,3,4- thiadiazole (200.0 mg, 0.86 mmol), K2CO 3 (357.0 mg, 2.58 mmol) and Pd(PPh 3 ) 4 (100.0 mg, 0.08 mmol) in a mixture of 1 ,4-dioxane (5 ml) and water (1 ml) was heated at 100 °C for 5 h under N2.
  • Step 2 To a solution of tert-butyl (4-(5-(trifluoromethyl)-1 ,3,4-thiadiazol-2- yl)phenyl)carbamate 1-10b (200.0 mg, 0.58 mmol) in MeOH (3 ml) was added a solution of HCI in 1 ,4-dioxane (725 ul, 4 M). The reaction was stirred at RT for 1 h. The pH was adjusted to 7-8 by addition of 2 M NaHCO 3 . The mixture was diluted with water (5 ml) and extracted with DCM (2 x 10 ml). The combined organics were dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 1 To a solution of 2-chloro-1-fluoro-4-nitrobenzene l-4a (1.0 g, 5.7 mmol) and oxetan- 3-ol (845 mg, 11.4 mmol) in DMF (20 ml) was added CS2CO 3 (5.6 g, 17.1 mol). The mixture was heated at 80 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 10 ml). The combined organics were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 2 To a solution of 3-(2-chloro-4-nitrophenoxy)oxetane 1-11a (900 mg, 3.9 mmol) in a mixture of EtOH (10 ml) and saturated aqueous NH 4 CI (10 ml) was added iron powder (1.7 g, 31.4 mmol). The reaction was heated at 80 °C for 16 h, cooled and filtered. The product was extracted from the filtrate with EtOAc (2 x 20 ml). The combined organics were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give 3-chloro-4-(oxetan-3- yloxy)aniline 1-11 as a grey solid.
  • Step 1 2-Chloro-1-((1s,3s)-3-methoxycyclobutoxy)-4-nitrobenzene 1-12a was synthesised from 2-chloro-1-fluoro-4-nitrobenzene l-4a and (1s,3s)-3-methoxycyclobutan-1-ol using a procedure essentially the same as 1-11 a.
  • Step 2 3-Chloro-4-((1s,3s)-3-methoxycyclobutoxy)aniline 1-12 was synthesized from 2- chloro-1-((1s,3s)-3-methoxycyclobutoxy)-4-nitrobenzene 1-12a using a procedure essentially the same as 1-11.
  • Step 1 To a solution of 4-amino-2-chloro-5-fluorophenol 1-13a (0.250 g, 1.55 mmol) in DCM (5 ml) was added di-tert-butyl dicarbonate (371 mg, 1.70 mmol). The resultant mixture was stirred at RT for 48 h. THF (5 ml) was added and a further portion of di-tert-butyl dicarbonate (169 mg, 774 ⁇ mol) followed by EtsN (216 ⁇ l, 1.55 mmol). The mixture was stirred at RT for 2 days.
  • Step 2 To a solution of tert- butyl (4-((tert-butoxycarbonyl)oxy)-5-chloro-2- fluorophenyl)carbamate 1-13b (200 mg, 547 ⁇ mol) in DCM (4 ml) was added morpholine (1.50 ml, 17.4 mmol) and the resulting mixture was stirred at RT overnight. The mixture was concentrated in vacuo. The product was purified by chromatography on silica gel (0-100% EtOAc/isohexane) to afford the product as a mixture containing morpholine. The material was taken up in DCM (15 ml) and washed with aq. 1 M HCI (2 x 15 ml).
  • Step 3 To a solution of tert-butyl (5-chloro-2-fluoro-4-hydroxyphenyl)carbamate 1-13c (144 mg, 479 ⁇ mol) in DMF (1.0 ml) was added potassium carbonate (165 mg, 1.20 mmol) and bromocyclobutane (55.6 ⁇ l, 575 ⁇ mol) and the resulting mixture was stirred at 100 °C for 4 h. After cooling, the mixture was diluted with EtOAc (20 ml) and brine (20 ml). The layers were separated, and the aqueous layer was further extracted with EtOAc (20 ml). The combined organics were washed with brine (2 x 20 ml), dried over MgSO4 and concentrated in vacuo.
  • Step 4 To a solution of tert-butyl (5-chloro-4-cyclobutoxy-2-fluorophenyl)carbamate 1-13d (50 mg, 0.16 mmol) in DCM (1.0 ml) was added HCI in dioxane (1.00 ml, 4.0 molar, 4.00 mmol) and the resulting mixture was stirred at RT for 16 h. The mixture was loaded onto SCX ( ⁇ 10 g) and the SCXwas washed with MeOH (50 ml) and then the product was eluted with 0.7 M NH 3 in MeOH (50 ml) to afford 5-chloro-4-cyclobutoxy-2-fluoroaniline 1-13 as a colourless oil.

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Abstract

Un aspect de l'invention concerne un composé de formule (I), ou un sel ou un solvant pharmaceutiquement acceptable de celui-ci, (I) : le cycle B représentant un groupe aromatique monocyclique ou un groupe hétéroaromatique monocyclique ou bicyclique, chacun étant éventuellement substitué par des groupes halogéno, CN, hydroxyle, alkyle, haloalkyle, cycloalkyle, halocycloalkyle, hydroxycycloalkyle, O-cycloalkyle, alcoxy, haloalkoxy, hétérocycloalkyle, O-hétérocycloalkyle, aryle, hétéroaryle, O-aryle, NHCO-alkényle, NHCO-aryle, -(CH2)q-O-hétéroaryle, CONH-aryl, aryloxy-alkyle, O-aralkyle et CO2-alkyle, lesdits groupes aryle, hétéroaryle, hétérocycloalkyle, O-cycloalkyle, NHCO-aryl, -(CH2)q-O-hétéroaryle, CONH-aryl, aryloxy-alkyle, O-aralkyle et O-aryle étant chacun éventuellement substitués par un ou plusieurs groupes choisis indépendamment parmi les groupes halothane, alkyle, haloalkyle, alcoxy, NHCO-alkyle, NR13R13', SO2-alkyle, CN, hydroxyalkyle, CONR14R14', alkyle-NR15R15', hétérocycloalkyle, alkyle-hétérocycloalkyle, alkyle-cycloalkyle, aryle, (CH2)m-NHSO2-alkyle, CO2R16, alcoxyalkyle, haloalkoxy, O-hétérocycloalkyle, hétéroaryle, alcoxy et O-(CH2)p-cycloalkyle, ce dernier groupe étant éventuellement substitué par un ou plusieurs groupes halo, haloalkyle, alkyle ou alcoxy ; m représentant un nombre entier compris entre 0 et 3 ; p et q représentant chacun indépendamment compris entre 0 et 3 ; Z représentant CR12 ; Y représentant CR10 R10', R10 et R10' étant chacun indépendamment choisi parmi les éléments H, F, alkyle et haloalkyle ; Ra et Rb étant chacun indépendamment choisi parmi les éléments H et alkyle ; R6 étant choisi parmi les éléments H, alkyle, cycloalkyle et hydroxyalkyle ; R12 étant choisi parmi les éléments H, alkyle, haloalkyle, halogéno, hydroxyle et O-alkyle ; et R13, R13', R14, R14', R15, R15' et R16 étant chacun choisi indépendamment parmi les éléments H, alkyle et alcoxyalkyle. D'autres aspects de l'invention concernent des composés de formule (I) destinés à être utilisés comme médicaments, en particulier dans le domaine de l'immuno-oncologie, de l'immunologie et des applications connexes.
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WO2021245427A1 (fr) 2020-06-05 2021-12-09 Pathios Therapeutics Limited N-phénylaminocarbonylpyridino-, pyrimidino et benzo-tropanes utilisés comme modulateurs de gpr65
WO2022136844A1 (fr) * 2020-12-22 2022-06-30 Pathios Therapeutics Limited Dérivés de n-(pyridin-2-yl)-6,7,8,9-tétrahydro-5h-5,8-epiminocyclohepta[c]pyridine-10-carboxamide et composés similaires servant de modulateurs de gpr65 pour traiter le cancer
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WO2021245427A1 (fr) 2020-06-05 2021-12-09 Pathios Therapeutics Limited N-phénylaminocarbonylpyridino-, pyrimidino et benzo-tropanes utilisés comme modulateurs de gpr65
WO2022136844A1 (fr) * 2020-12-22 2022-06-30 Pathios Therapeutics Limited Dérivés de n-(pyridin-2-yl)-6,7,8,9-tétrahydro-5h-5,8-epiminocyclohepta[c]pyridine-10-carboxamide et composés similaires servant de modulateurs de gpr65 pour traiter le cancer
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